Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases

Qian       Ren; Lu       Cheng; Jing       Yi; Liang       Ma; Jing       Pan; Shen-Ju       Gou; Ping       Fu
Abstract

Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.
Keywords: Toll-like receptors, innate immunity, kidney diseases, therapy, glomerulonephritis, dysfunction.
[1] 
Wang, Y.H.; Zhang, Y.G. Kidney and innate immunity. Immunol. Lett.,  2017, 183, 73-78.
[http://dx.doi.org/10.1016/j.imlet.2017.01.011 ] [PMID:  28143791] 
[2] 
Pelka, K.; Shibata, T.; Miyake, K.; Latz, E. Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology. Immunol. Rev.,  2016, 269(1), 60-75.
[http://dx.doi.org/10.1111/imr.12375 ] [PMID:  26683145] 
[3] 
Barton, G.M.; Kagan, J.C.; Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol.,  2006, 7(1), 49-56.
[http://dx.doi.org/10.1038/ni1280 ] [PMID:  16341217] 
[4] 
Gao, W.; Xiong, Y.; Li, Q.; Yang, H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front. Physiol.,  2017, 8, 508.
[http://dx.doi.org/10.3389/fphys.2017.00508 ] [PMID:  28769820] 
[5] 
Hato, T.; Dagher, P.C. How the innate immune system senses trouble and causes trouble. Clin. J. Am. Soc. Nephrol.,  2015, 10(8), 1459-1469.
[http://dx.doi.org/10.2215/CJN.04680514 ] [PMID:  25414319] 
[6] 
Godaly, G.; Ambite, I.; Svanborg, C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr. Opin. Infect. Dis.,  2015, 28(1), 88-96.
[http://dx.doi.org/10.1097/QCO.0000000000000127 ] [PMID:  25539411] 
[7] 
Karananou, P.; Fleva, A.; Tramma, D.; Alataki, A.; Pavlitou-Tsiontsi, A. Emporiadou-Peticopoulou, M. Altered expression of TLR2 and TLR4 on peripheral CD14+ blood monocytes in children with urinary tract infection[J]altered expression of TLR2 and TLR4 on peripheral CD14+ blood monocytes in children with urinary tract infection. BioMed Res. Int., 2016.,6052891.
[http://dx.doi.org/10.1155/2016/6052891 ] [PMID:  27252945] 
[8] 
Yin, X.; Hou, T.; Liu, Y.; Chen, J.; Yao, Z.; Ma, C.; Yang, L.; Wei, L. Association of Toll-like receptor 4 gene polymorphism and expression with urinary tract infection types in adults. PLoS One,  2010, 5(12),e14223.
[http://dx.doi.org/10.1371/journal.pone.0014223 ] [PMID:  21151974] 
[9] 
Hawn, T.R.; Scholes, D.; Li, S.S.; Wang, H.; Yang, Y.; Roberts, P.L.; Stapleton, A.E.; Janer, M.; Aderem, A.; Stamm, W.E.; Zhao, L.P.; Hooton, T.M. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One,  2009, 4(6),e5990.
[http://dx.doi.org/10.1371/journal.pone.0005990 ] [PMID:  19543401] 
[10] 
Cheng, C.H.; Lee, Y.S.; Chang, C.J.; Lin, T.Y. Genetic polymorphisms in Toll-like receptors among pediatric patients with renal parenchymal infections of different clinical severities. PLoS One,  2013, 8(3),e58687.
[http://dx.doi.org/10.1371/journal.pone.0058687 ] [PMID:  23484049] 
[11] 
Tabel, Y.; Berdeli, A.; Mir, S. Association of TLR2 gene Arg753Gln polymorphism with urinary tract infection in children. Int. J. Immunogenet.,  2007, 34(6), 399-405.
[http://dx.doi.org/10.1111/j.1744-313X.2007.00709.x ] [PMID:  18001294] 
[12] 
Ragnarsdóttir, B.; Samuelsson, M.; Gustafsson, M.C.; Leijonhufvud, I.; Karpman, D.; Svanborg, C. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis.,  2007, 196(3), 475-484.
[http://dx.doi.org/10.1086/518893 ] [PMID:  17597463] 
[13] 
Gond, D.P.; Singh, S.; Agrawal, N.K. Testing an association between TLR4 and CXCR1 gene polymorphisms with susceptibility to urinary tract infection in type 2 diabetes in north Indian population. Gene,  2018, 641, 196-202.
[http://dx.doi.org/10.1016/j.gene.2017.10.060 ] [PMID:  29066305] 
[14] 
Bayram, M.T.; Soylu, A.; Ateş, H.; Kızıldağ, S.; Kavukçu, S. TLR-4 polymorphisms and leukocyte TLR-4 expression in febrile UTI and renal scarring. Pediatr. Nephrol.,  2013, 28(9), 1827-1835.
[http://dx.doi.org/10.1007/s00467-013-2478-8 ] [PMID:  23612767] 
[15] 
Chatzi, M.; Papanikolaou, J.; Makris, D.; Papathanasiou, I.; Tsezou, A.; Karvouniaris, M.; Zakynthinos, E. Toll-like receptor 2, 4 and 9 polymorphisms and their association with ICU-acquired infections in Central Greece. J. Crit. Care,  2018, 47, 1-8.
[http://dx.doi.org/10.1016/j.jcrc.2018.05.012 ] [PMID:  29860039] 
[16] 
Castro-Alarcon, N.; Rodriguez-Garcia, R.; Ruiz-Rosas, M.; Munoz-Valle, J.F.; Guzman-Guzman, I.P.; Parra-Rojas, I. Association between TLR4 polymorphisms (896 A>G, 1196 C>T, - 2570 A>G, - 2081 G>A) and virulence factors in uropathogenic Escherichia coli. Clin. Exp. Med.,  2019, 19(1), 105-113.
[http://dx.doi.org/10.1007/s10238-018-0527-0 ] [PMID:  30220001] 
[17] 
Akil, I.; Ozkinay, F.; Onay, H.; Canda, E.; Gumuser, G.; Kavukcu, S. Assessment of Toll-like receptor-4 gene polymorphism on pyelonephritis and renal scar. Int. J. Immunogenet.,  2012, 39(4), 303-307.
[http://dx.doi.org/10.1111/j.1744-313X.2012.01090.x ] [PMID:  22308961] 
[18] 
van der Starre, W.E.; van Nieuwkoop, C.; Thomson, U.; Zijderveld-Voshart, M.S.; Koopman, J.P.; van der Reijden, T.J.; van Dissel, J.T.; van de Vosse, E. Urinary proteins, vitamin D and genetic polymorphisms as risk factors for febrile urinary tract infection and relation with bacteremia: a case control study. PLoS One,  2015, 10(3),e0121302.
[http://dx.doi.org/10.1371/journal.pone.0121302 ] [PMID:  25807366] 
[19] 
Chowdhury, P.; Sacks, S.H.; Sheerin, N.S. Toll-like receptors TLR2 and TLR4 initiate the innate immune response of the renal tubular epithelium to bacterial products. Clin. Exp. Immunol.,  2006, 145(2), 346-356.
[http://dx.doi.org/10.1111/j.1365-2249.2006.03116.x ] [PMID:  16879256] 
[20] 
Zhang, D.; Zhang, G.; Hayden, M.S.; Greenblatt, M.B.; Bussey, C.; Flavell, R.A.; Ghosh, S. A toll-like receptor that prevents infection by uropathogenic bacteria. Science,  2004, 303(5663), 1522-1526.
[http://dx.doi.org/10.1126/science.1094351 ] [PMID:  15001781] 
[21] 
Andersen-Nissen, E.; Hawn, T.R.; Smith, K.D.; Nachman, A.; Lampano, A.E. Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol.,  2007, 178(8), 4717-4720.
[http://dx.doi.org/10.4049/jimmunol.178.8.4717 ] [PMID:  17404249] 
[22] 
Foust-Wright, C.E.; Pulliam, S.J.; Batalden, R.P.; Berk, T.K.; Weinstein, M.M.; Wakamatsu, M.M.; Phillippe, M. Hormone modulation of toll-like receptor 5 in cultured human bladder epithelial cells. Reprod. Sci.,  2017, 24(5), 713-719.
[http://dx.doi.org/10.1177/1933719116667489 ] [PMID:  27651177] 
[23] 
Bens, M.; Vimont, S.; Ben Mkaddem, S.; Chassin, C.; Goujon, J.M.; Balloy, V.; Chignard, M.; Werts, C.; Vandewalle, A. Flagellin/TLR5 signalling activates renal collecting duct cells and facilitates invasion and cellular translocation of uropathogenic Escherichia coli. Cell. Microbiol.,  2014, 16(10), 1503-1517.
[http://dx.doi.org/10.1111/cmi.12306 ] [PMID:  24779433] 
[24] 
Samuelsson, P.; Hang, L.; Wullt, B.; Irjala, H.; Svanborg, C. Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa. Infect. Immun.,  2004, 72(6), 3179-3186.
[http://dx.doi.org/10.1128/IAI.72.6.3179-3186.2004 ] [PMID:  15155619] 
[25] 
Abraham, S.N.; Miao, Y. The nature of immune responses to urinary tract infections. Nat. Rev. Immunol.,  2015, 15(10), 655-663.
[http://dx.doi.org/10.1038/nri3887 ] [PMID:  26388331] 
[26] 
Bishop, B.L.; Duncan, M.J.; Song, J.; Li, G.; Zaas, D.; Abraham, S.N. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med.,  2007, 13(5), 625-630.
[http://dx.doi.org/10.1038/nm1572 ] [PMID:  17417648] 
[27] 
Good, D.W.; George, T.; Watts, B.A. III Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am. J. Physiol. Renal Physiol.,  2009, 297(4), F866-F874.
[http://dx.doi.org/10.1152/ajprenal.00335.2009 ] [PMID:  19625374] 
[28] 
Chassin, C.; Vimont, S.; Cluzeaud, F.; Bens, M.; Goujon, J.M.; Fernandez, B.; Hertig, A.; Rondeau, E.; Arlet, G.; Hornef, M.W.; Vandewalle, A. TLR4 facilitates translocation of bacteria across renal collecting duct cells. J. Am. Soc. Nephrol.,  2008, 19(12), 2364-2374.
[http://dx.doi.org/10.1681/ASN.2007121273 ] [PMID:  18753256] 
[29] 
Chassin, C.; Goujon, J.M.; Darche, S.; du Merle, L.; Bens, M.; Cluzeaud, F. Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways. J. Immunol.,  2006, 177(7), 4773-4784.
[30] 
Patole, P.S.; Schubert, S.; Hildinger, K.; Khandoga, S.; Khandoga, A.; Segerer, S.; Henger, A.; Kretzler, M.; Werner, M.; Krombach, F.; Schlöndorff, D.; Anders, H.J. Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney Int.,  2005, 68(6), 2582-2587.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00729.x ] [PMID:  16316333] 
[31] 
Morosanova, M.A.; Plotnikov, E.Y.; Zorova, L.D.; Pevzner, I.B.; Popkov, V.A.; Silachev, D.N.; Jankauskas, S.S.; Babenko, V.A.; Zorov, D.B. Mechanisms of inflammatory injury of renal tubular cells in a cellular model of pyelonephritis. Biochemistry (Mosc.),  2016, 81(11), 1240-1250.
[http://dx.doi.org/10.1134/S000629791611002X ] [PMID:  27914450] 
[32] 
Couser, W.G.; Johnson, R.J. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int.,  2014, 86(5), 905-914.
[http://dx.doi.org/10.1038/ki.2014.49 ] [PMID:  24621918] 
[33] 
Muto, M.; Manfroi, B.; Suzuki, H.; Joh, K.; Nagai, M.; Wakai, S.; Righini, C.; Maiguma, M.; Izui, S.; Tomino, Y.; Huard, B.; Suzuki, Y. Toll-like receptor 9 stimulation induces aberrant expression of a proliferation-inducing ligand by tonsillar germinal center B cells in IgA nephropathy. J. Am. Soc. Nephrol.,  2017, 28(4), 1227-1238.
[http://dx.doi.org/10.1681/ASN.2016050496 ] [PMID:  27920152] 
[34] 
He, L.; Peng, X.; Wang, J.; Tang, C.; Zhou, X.; Liu, H.; Liu, F.; Sun, L.; Peng, Y. Synthetic double-stranded RNA poly(I:C) aggravates IgA nephropathy by Triggering IgA class switching recombination through the TLR3-BAFF axis. Am. J. Nephrol.,  2015, 42(3), 185-197.
[http://dx.doi.org/10.1159/000440819 ] [PMID:  26417991] 
[35] 
Li, W.; Peng, X.; Liu, Y.; Liu, H.; Liu, F.; He, L.; Liu, Y.; Zhang, F.; Guo, C.; Chen, G.; Zhang, L.; Dong, Z.; Peng, Y. TLR9 and BAFF: their expression in patients with IgA nephropathy. Mol. Med. Rep.,  2014, 10(3), 1469-1474.
[http://dx.doi.org/10.3892/mmr.2014.2359 ] [PMID:  24993857] 
[36] 
Saito, A.; Komatsuda, A.; Kaga, H.; Sato, R.; Togashi, M.; Okuyama, S.; Wakui, H.; Takahashi, N. Different expression patterns of toll-like receptor mRNAs in blood mononuclear cells of IgA nephropathy and IgA vasculitis with nephritis. Tohoku J. Exp. Med.,  2016, 240(3), 199-208.
[http://dx.doi.org/10.1620/tjem.240.199 ] [PMID:  27818460] 
[37] 
Anders, H.J. Toll-like receptors and danger signaling in kidney injury. J. Am. Soc. Nephrol.,  2010, 21(8), 1270-1274.
[http://dx.doi.org/10.1681/ASN.2010030233 ] [PMID:  20651159] 
[38] 
Gao, J.; Wei, L.; Wei, J.; Yao, G.; Wang, L.; Wang, M.; Liu, X.; Dai, C.; Jin, T.; Dai, Z.; Fu, R. TLR1 polymorphism rs4833095 as a risk factor for IgA nephropathy in a Chinese Han population: A case-control study. Oncotarget,  2016, 7(50), 83031-83039.
[http://dx.doi.org/10.18632/oncotarget.12965 ] [PMID:  27806314] 
[39] 
Sallustio, F.; Cox, S.N.; Serino, G.; Curci, C.; Pesce, F.; De Palma, G.; Papagianni, A.; Kirmizis, D.; Falchi, M.; Schena, F.P. European IgAN consortium. Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients. Eur. J. Hum. Genet.,  2015, 23(7), 940-948.
[http://dx.doi.org/10.1038/ejhg.2014.208 ] [PMID:  25293716] 
[40] 
Coppo, R.; Camilla, R.; Amore, A.; Peruzzi, L.; Daprà, V.; Loiacono, E.; Vatrano, S.; Rollino, C.; Sepe, V.; Rampino, T.; Dal Canton, A. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin. Exp. Immunol.,  2010, 159(1), 73-81.
[http://dx.doi.org/10.1111/j.1365-2249.2009.04045.x ] [PMID:  19891659] 
[41] 
Zou, J.N.; Xiao, J.; Hu, S.S.; Fu, C.S.; Zhang, X.L.; Zhang, Z.X.; Lu, Y.J.; Chen, W.J.; Ye, Z.B. Toll-like receptor 4 signaling pathway in the protective effect of pioglitazone on experimental immunoglobulin A nephropathy. Chin. Med. J. (Engl.),  2017, 130(8), 906-913.
[http://dx.doi.org/10.4103/0366-6999.204101 ] [PMID:  28397719] 
[42] 
Maiguma, M.; Suzuki, Y.; Suzuki, H.; Okazaki, K.; Aizawa, M.; Muto, M.; Tomino, Y. Dietary zinc is a key environmental modifier in the progression of IgA nephropathy. PLoS One,  2014, 9(2),e90558.
[http://dx.doi.org/10.1371/journal.pone.0090558 ] [PMID:  24587392] 
[43] 
Bauman, D.R.; Bitmansour, A.D.; McDonald, J.G.; Thompson, B.M.; Liang, G.; Russell, D.W. 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proc. Natl. Acad. Sci. USA,  2009, 106(39), 16764-16769.
[http://dx.doi.org/10.1073/pnas.0909142106 ] [PMID:  19805370] 
[44] 
Kajiyama, T.; Suzuki, Y.; Kihara, M.; Suzuki, H.; Horikoshi, S.; Tomino, Y. Different pathological roles of toll-like receptor 9 on mucosal B cells and dendritic cells in murine IgA nephropathy. Clin. Dev. Immunol.,  2011, 2011,819646.
[http://dx.doi.org/10.1155/2011/819646 ] [PMID:  21765852] 
[45] 
Suzuki, H.; Suzuki, Y.; Narita, I.; Aizawa, M.; Kihara, M.; Yamanaka, T.; Kanou, T.; Tsukaguchi, H.; Novak, J.; Horikoshi, S.; Tomino, Y. Toll-like receptor 9 affects severity of IgA nephropathy. J. Am. Soc. Nephrol.,  2008, 19(12), 2384-2395.
[http://dx.doi.org/10.1681/ASN.2007121311 ] [PMID:  18776126] 
[46] 
Zheng, N.; Wang, B.; Fan, J.; Luo, N.; Kong, Q.; Ye, H.; Zhang, J.; Ming, H.; Yu, X. Increased abundance of plasmacytoid dendritic cells and interferon-alpha induces plasma cell differentiation in patients of IgA nephropathy. Mediators Inflamm.,  2017, 2017,4532409.
[http://dx.doi.org/10.1155/2017/4532409 ] [PMID:  29403161] 
[47] 
Celhar, T.; Fairhurst, A.M. Toll-like receptors in systemic lupus erythematosus: potential for personalized treatment. Front. Pharmacol.,  2014, 5, 265.
[http://dx.doi.org/10.3389/fphar.2014.00265 ] [PMID:  25538618] 
[48] 
Lindau, D.; Mussard, J.; Rabsteyn, A.; Ribon, M.; Kötter, I.; Igney, A.; Adema, G.J.; Boissier, M.C.; Rammensee, H.G.; Decker, P. TLR9 independent interferon α production by neutrophils on NETosis in response to circulating chromatin, a key lupus autoantigen. Ann. Rheum. Dis.,  2014, 73(12), 2199-2207.
[http://dx.doi.org/10.1136/annrheumdis-2012-203041 ] [PMID:  24013727] 
[49] 
Conti, F.; Spinelli, F.R.; Truglia, S.; Miranda, F.; Alessandri, C.; Ceccarelli, F.; Bombardieri, M.; Giannakakis, K.; Valesini, G. Kidney expression of toll like receptors in lupus nephritis: quantification and clinicopathological correlations. Mediators Inflamm.,  2016, 2016,7697592.
[http://dx.doi.org/10.1155/2016/7697592 ] [PMID:  27635115] 
[50] 
Devarapu, S.K.; Anders, H.J. Toll-like receptors in lupus nephritis. J. Biomed. Sci.,  2018, 25(1), 35.
[http://dx.doi.org/10.1186/s12929-018-0436-2 ] [PMID:  29650017] 
[51] 
Teichmann, L.L.; Schenten, D.; Medzhitov, R.; Kashgarian, M.; Shlomchik, M.J. Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity,  2013, 38(3), 528-540.
[http://dx.doi.org/10.1016/j.immuni.2012.11.017 ] [PMID:  23499488] 
[52] 
Capolunghi, F.; Rosado, M.M.; Cascioli, S.; Girolami, E.; Bordasco, S.; Vivarelli, M.; Ruggiero, B.; Cortis, E.; Insalaco, A.; Fantò, N.; Gallo, G.; Nucera, E.; Loiarro, M.; Sette, C.; De Santis, R.; Carsetti, R.; Ruggiero, V. Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients. Rheumatology (Oxford),  2010, 49(12), 2281-2289.
[http://dx.doi.org/10.1093/rheumatology/keq226 ] [PMID:  20739362] 
[53] 
Sadanaga, A.; Nakashima, H.; Akahoshi, M.; Masutani, K.; Miyake, K.; Igawa, T.; Sugiyama, N.; Niiro, H.; Harada, M. Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum.,  2007, 56(5), 1618-1628.
[http://dx.doi.org/10.1002/art.22571 ] [PMID:  17469144] 
[54] 
Hua, Z.; Gross, A.J.; Lamagna, C.; Ramos-Hernandez, N.; Scapini, P.; DeFranco, A.L. Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. J. Immunol.,  2014, 192(3), 875-885.
[http://dx.doi.org/10.4049/jimmunol.1300683 ] [PMID:  24379120] 
[55] 
Laska, M.J.; Troldborg, A.; Hansen, B.; Stengaard-Pedersen, K.; Junker, P.; Nexø, B.A.; Voss, A. Polymorphisms within toll-like receptors are associated with systemic lupus erythematosus in a cohort of Danish females. Rheumatology (Oxford),  2014, 53(1), 48-55.
[http://dx.doi.org/10.1093/rheumatology/ket316 ] [PMID:  24064706] 
[56] 
Wang, C.M.; Chang, S.W.; Wu, Y.J.; Lin, J.C.; Ho, H.H.; Chou, T.C.; Yang, B.; Wu, J.; Chen, J.Y. Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population. Sci. Rep.,  2014, 4, 3792.
[http://dx.doi.org/10.1038/srep03792 ] [PMID:  24445780] 
[57] 
Hwang, S.H.; Lee, H.; Yamamoto, M.; Jones, L.A.; Dayalan, J.; Hopkins, R. B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice. J. Immunol.,  2012, 189(12), 5786-5796.
[http://dx.doi.org/10.4049/jimmunol.1202195 ] [PMID:  23150717] 
[58] 
Soni, C.; Wong, E.B.; Domeier, P.P.; Khan, T.N.; Satoh, T.; Akira, S. Rahman, Z.S.M. B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J. Immunol.,  2014, 193(9), 4400-4414.
[http://dx.doi.org/10.4049/jimmunol.1401720 ] [PMID:  25252960] 
[59] 
Khoryati, L.; Augusto, J.F.; Shipley, E.; Contin-Bordes, C.; Douchet, I.; Mitrovic, S.; Truchetet, M.E.; Lazaro, E.; Duffau, P.; Couzi, L.; Jacquemin, C.; Barnetche, T.; Vacher, P.; Schaeverbeke, T.; Blanco, P.; Richez, C. Fédération Hospitalo-Universitaire ACRONIM. IgE inhibits toll-like receptor 7- and toll-like receptor 9-mediated expression of interferon-α by plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Arthritis Rheumatol.,  2016, 68(9), 2221-2231.
[http://dx.doi.org/10.1002/art.39679 ] [PMID:  26991804] 
[60] 
Jackson, S.W.; Scharping, N.E.; Kolhatkar, N.S.; Khim, S.; Schwartz, M.A. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J. Immunol.,  2014, 192(10), 4525-4532.
[http://dx.doi.org/10.4049/jimmunol.1400098 ] [PMID:  24711620] 
[61] 
Fukui, R.; Saitoh, S.; Kanno, A.; Onji, M.; Shibata, T.; Ito, A.; Onji, M.; Matsumoto, M.; Akira, S.; Yoshida, N.; Miyake, K. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity,  2011, 35(1), 69-81.
[http://dx.doi.org/10.1016/j.immuni.2011.05.010 ] [PMID:  21683627] 
[62] 
Yuan, Y.; Yang, M.; Wang, K.; Sun, J.; Song, L.; Diao, X.; Jiang, Z.; Cheng, G.; Wang, X. Excessive activation of the TLR9/TGF-β1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus. Arthritis Res. Ther.,  2017, 19(1), 70.
[http://dx.doi.org/10.1186/s13075-017-1238-8 ] [PMID:  28356164] 
[63] 
Bossaller, L.; Christ, A.; Pelka, K.; Nundel, K.; Chiang, P.I.; Pang, C. TLR9 deficiency leads to accelerated renal disease and myeloid lineage abnormalities in pristane-induced murine lupus. J. Immunol.,  2016, 197(4), 1044-1053.
[http://dx.doi.org/10.4049/jimmunol.1501943 ] [PMID:  27354219] 
[64] 
Nickerson, K.M.; Christensen, S.R.; Shupe, J.; Kashgarian, M.; Kim, D.; Elkon, K. TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J. Immunol.,  2010, 184(4), 1840-1848.
[http://dx.doi.org/10.4049/jimmunol.0902592 ] [PMID:  20089701] 
[65] 
Celhar, T.; Yasuga, H.; Lee, H.Y.; Zharkova, O.; Tripathi, S.; Thornhill, S.I.; Lu, H.K.; Au, B.; Lim, L.H.K.; Thamboo, T.P.; Akira, S.; Wakeland, E.K.; Connolly, J.E.; Fairhurst, A.M. Toll-Like receptor 9 deficiency breaks tolerance to RNA-associated antigens and up-regulates toll-like receptor 7 protein in SLE1 mice. Arthritis Rheumatol.,  2018, 70(10), 1597-1609.
[http://dx.doi.org/10.1002/art.40535 ] [PMID:  29687651] 
[66] 
Mande, P.; Zirak, B.; Ko, W.C.; Taravati, K.; Bride, K.L.; Brodeur, T.Y.; Deng, A.; Dresser, K.; Jiang, Z.; Ettinger, R.; Fitzgerald, K.A.; Rosenblum, M.D.; Harris, J.E.; Marshak-Rothstein, A. Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation. J. Clin. Invest.,  2018, 128(7), 2966-2978.
[http://dx.doi.org/10.1172/JCI98219 ] [PMID:  29889098] 
[67] 
Desnues, B.; Macedo, A.B.; Roussel-Queval, A.; Bonnardel, J.; Henri, S.; Demaria, O.; Alexopoulou, L. TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. Proc. Natl. Acad. Sci. USA,  2014, 111(4), 1497-1502.
[http://dx.doi.org/10.1073/pnas.1314121111 ] [PMID:  24474776] 
[68] 
Umiker, B.R.; Andersson, S.; Fernandez, L.; Korgaokar, P.; Larbi, A.; Pilichowska, M.; Weinkauf, C.C.; Wortis, H.H.; Kearney, J.F.; Imanishi-Kari, T. Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus. Eur. J. Immunol.,  2014, 44(5), 1503-1516.
[http://dx.doi.org/10.1002/eji.201344283 ] [PMID:  24500834] 
[69] 
Young, N.A.; Wu, L.C.; Burd, C.J.; Friedman, A.K.; Kaffenberger, B.H.; Rajaram, M.V.; Schlesinger, L.S.; James, H.; Shupnik, M.A.; Jarjour, W.N. Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus. Clin. Immunol.,  2014, 151(1), 66-77.
[http://dx.doi.org/10.1016/j.clim.2014.01.006 ] [PMID:  24525049] 
[70] 
Kimura, J.; Ichii, O.; Miyazono, K.; Nakamura, T.; Horino, T.; Otsuka-Kanazawa, S.; Kon, Y. Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis. Sci. Rep.,  2014, 4, 7290.
[http://dx.doi.org/10.1038/srep07290 ] [PMID:  25468389] 
[71] 
Imaizumi, T.; Aizawa, T.; Hayakari, R.; Xing, F.; Meng, P.; Tsuruga, K.; Matsumiya, T.; Yoshida, H.; Wang, L.; Tatsuta, T.; Tanaka, H. Tumor necrosis factor-α synergistically enhances polyinosinic-polycytidylic acid-induced toll-like receptor 3 signaling in cultured normal human mesangial cells: possible involvement in the pathogenesis of lupus nephritis. Clin. Exp. Nephrol.,  2015, 19(1), 75-81.
[http://dx.doi.org/10.1007/s10157-014-0956-3 ] [PMID:  24627031] 
[72] 
Elloumi, N.; Fakhfakh, R.; Abida, O.; Ayadi, L.; Marzouk, S.; Hachicha, H.; Fourati, M.; Bahloul, Z.; Mhiri, M.N.; Kammoun, K.; Masmoudi, H. Relevant genetic polymorphisms and kidney expression of Toll-like receptor (TLR)-5 and TLR-9 in lupus nephritis. Clin. Exp. Immunol.,  2017, 190(3), 328-339.
[http://dx.doi.org/10.1111/cei.13022 ] [PMID:  28763101] 
[73] 
Lorenz, G.; Lech, M.; Anders, H.J. Toll-like receptor activation in the pathogenesis of lupus nephritis. Clin. Immunol.,  2017, 185, 86-94.
[http://dx.doi.org/10.1016/j.clim.2016.07.015 ] [PMID:  27423476] 
[74] 
Lartigue, A.; Colliou, N.; Calbo, S.; Francois, A.; Jacquot, S. Critical role of TLR2 and TLR4 in autoantibody production and glomerulonephritis in lpr mutation-induced mouse lupus. J. Immunol.,  2017, 183(10), 6207-6216.
[http://dx.doi.org/10.4049/jimmunol.0803219 ] [PMID:  19841185] 
[75] 
Summers, S.A.; Hoi, A.; Steinmetz, O.M.; O’Sullivan, K.M.; Ooi, J.D.; Odobasic, D.; Akira, S.; Kitching, A.R.; Holdsworth, S.R. TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy. J. Autoimmun.,  2010, 35(4), 291-298.
[http://dx.doi.org/10.1016/j.jaut.2010.05.004 ] [PMID:  20810248] 
[76] 
Feng, X.J.; Wu, C.; Yan, G.F.; Liu, Q.J.; Liu, J.X.; Hao, J. TLR2 plays a critical role in HMGB1-induced glomeruli cell proliferation through the FoxO1 signaling pathway in lupus nephritis. J. Interferon Cytokine Res.,  2016, 36(4), 258-266.
[http://dx.doi.org/10.1089/jir.2015.0082 ] [PMID:  26799193] 
[77] 
Wirestam, L.; Schierbeck, H.; Skogh, T.; Gunnarsson, I.; Ottosson, L.; Erlandsson-Harris, H.; Wetterö, J.; Sjöwall, C. Antibodies against high mobility group box protein-1 (HMGB1) versus other anti-nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus. Arthritis Res. Ther.,  2015, 17, 338.
[http://dx.doi.org/10.1186/s13075-015-0856-2 ] [PMID:  26596890] 
[78] 
Svenson, J.; Cunningham, M.; Dasgupta, S.; Gilkeson, G.S. Estrogen receptor alpha modulates mesangial cell responses to toll-like receptor ligands. Am. J. Med. Sci.,  2014, 348(6), 492-500.
[http://dx.doi.org/10.1097/MAJ.0000000000000339 ] [PMID:  25343264] 
[79] 
Hu, C.; Sun, L.; Xiao, L.; Han, Y.; Fu, X.; Xiong, X.; Xu, X.; Liu, Y.; Yang, S.; Liu, F.; Kanwar, Y.S. Insights into the mechanisms involved in the expression and regulation of extracellular matrix proteins in diabetic nephropathy. Curr. Med. Chem.,  2015, 22(24), 2858-2870.
[http://dx.doi.org/10.2174/0929867322666150625095407 ] [PMID:  26119175] 
[80] 
Wada, J.; Makino, H. Innate immunity in diabetes and diabetic nephropathy. Nat. Rev. Nephrol.,  2016, 12(1), 13-26.
[http://dx.doi.org/10.1038/nrneph.2015.175 ] [PMID:  26568190] 
[81] 
Feng, Y.; Yang, S.; Ma, Y.; Bai, X.Y.; Chen, X. Role of Toll-like receptors in diabetic renal lesions in a miniature pig model. Sci. Adv.,  2015, 1(5),e1400183.
[http://dx.doi.org/10.1126/sciadv.1400183 ] [PMID:  26601192] 
[82] 
Mudaliar, H.; Pollock, C.; Panchapakesan, U. Role of Toll-like receptors in diabetic nephropathy. Clin. Sci. ,  2014, 126(10), 685-694.
[http://dx.doi.org/10.1042/CS20130267 ] [PMID:  24490813] 
[83] 
Velloso, L.A.; Folli, F.; Saad, M.J. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr. Rev.,  2015, 36(3), 245-271.
[http://dx.doi.org/10.1210/er.2014-1100 ] [PMID:  25811237] 
[84] 
Garibotto, G.; Carta, A.; Picciotto, D.; Viazzi, F.; Verzola, D. Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy. J. Nephrol.,  2017, 30(6), 719-727.
[http://dx.doi.org/10.1007/s40620-017-0432-8 ] [PMID:  28933050] 
[85] 
Cani, P.D.; Amar, J.; Iglesias, M.A.; Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.; Chabo, C.; Waget, A.; Delmée, E.; Cousin, B.; Sulpice, T.; Chamontin, B.; Ferrières, J.; Tanti, J.F.; Gibson, G.R.; Casteilla, L.; Delzenne, N.M.; Alessi, M.C.; Burcelin, R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes,  2007, 56(7), 1761-1772.
[http://dx.doi.org/10.2337/db06-1491 ] [PMID:  17456850] 
[86] 
Panchapakesan, U.; Pollock, C. The role of toll-like receptors in diabetic kidney disease. Curr. Opin. Nephrol. Hypertens.,  2018, 27(1), 30-34.
[http://dx.doi.org/10.1097/MNH.0000000000000377 ] [PMID:  29059081] 
[87] 
Peng, J.; Zheng, H.; Wang, X.; Cheng, Z. Upregulation of TLR4 via PKC activation contributes to impaired wound healing in high-glucose-treated kidney proximal tubular cells. PLoS One,  2017, 12(5),e0178147.
[http://dx.doi.org/10.1371/journal.pone.0178147 ] [PMID:  28542370] 
[88] 
Kuwabara, T.; Mori, K.; Mukoyama, M.; Kasahara, M.; Yokoi, H.; Nakao, K. Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy. Clin. Exp. Nephrol.,  2014, 18(4), 584-592.
[http://dx.doi.org/10.1007/s10157-013-0922-5 ] [PMID:  24357461] 
[89] 
Ma, J.; Chadban, S.J.; Zhao, C.Y.; Chen, X.; Kwan, T.; Panchapakesan, U.; Pollock, C.A.; Wu, H. TLR4 activation promotes podocyte injury and interstitial fibrosis in diabetic nephropathy. PLoS One,  2014, 9(5),e97985.
[http://dx.doi.org/10.1371/journal.pone.0097985 ] [PMID:  24842252] 
[90] 
Jialal, I.; Major, A.M.; Devaraj, S. Global Toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy. J. Diabetes Complications,  2014, 28(6), 755-761.
[http://dx.doi.org/10.1016/j.jdiacomp.2014.07.003 ] [PMID:  25116192] 
[91] 
Lv, J.; Chen, Q.; Shao, Y.; Chen, Y.; Shi, J. Cross-talk between angiotensin-II and toll-like receptor 4 triggers a synergetic inflammatory response in rat mesangial cells under high glucose conditions. Biochem. Biophys. Res. Commun.,  2015, 459(2), 264-269.
[http://dx.doi.org/10.1016/j.bbrc.2015.02.096 ] [PMID:  25732086] 
[92] 
Verzola, D.; Cappuccino, L.; D’Amato, E.; Villaggio, B.; Gianiorio, F.; Mij, M.; Simonato, A.; Viazzi, F.; Salvidio, G.; Garibotto, G. Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int.,  2014, 86(6), 1229-1243.
[http://dx.doi.org/10.1038/ki.2014.116 ] [PMID:  24786705] 
[93] 
Lin, M.; Yiu, W.H.; Wu, H.J.; Chan, L.Y.; Leung, J.C.; Au, W.S.; Chan, K.W.; Lai, K.N.; Tang, S.C. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J. Am. Soc. Nephrol.,  2012, 23(1), 86-102.
[http://dx.doi.org/10.1681/ASN.2010111210 ] [PMID:  22021706] 
[94] 
Cha, J.J.; Hyun, Y.Y.; Lee, M.H.; Kim, J.E.; Nam, D.H.; Song, H.K.; Kang, Y.S.; Lee, J.E.; Kim, H.W.; Han, J.Y.; Cha, D.R. Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice. Endocrinology,  2013, 154(6), 2144-2155.
[http://dx.doi.org/10.1210/en.2012-2080 ] [PMID:  23568555] 
[95] 
Lin, M.; Yiu, W.H.; Li, R.X.; Wu, H.J.; Wong, D.W.; Chan, L.Y.; Leung, J.C.; Lai, K.N.; Tang, S.C. The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int.,  2013, 83(5), 887-900.
[http://dx.doi.org/10.1038/ki.2013.11 ] [PMID:  23423259] 
[96] 
Dasu, M.R.; Devaraj, S.; Park, S.; Jialal, I. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care,  2010, 33(4), 861-868.
[http://dx.doi.org/10.2337/dc09-1799 ] [PMID:  20067962] 
[97] 
Ma, J.; Wu, H.; Zhao, C.Y.; Panchapakesan, U.; Pollock, C.; Chadban, S.J. Requirement for TLR2 in the development of albuminuria, inflammation and fibrosis in experimental diabetic nephropathy. Int. J. Clin. Exp. Pathol.,  2014, 7(2), 481-495.
[PMID:  24551269] 
[98] 
Li, F.; Zhang, N.; Li, Z.; Deng, L.; Zhang, J.; Zhou, Y. Toll-like receptor 2 agonist exacerbates renal injury in diabetic mice. Exp. Ther. Med.,  2017, 13(2), 495-502.
[http://dx.doi.org/10.3892/etm.2017.4031 ] [PMID:  28352321] 
[99] 
Ehses, J.A.; Meier, D.T.; Wueest, S.; Rytka, J.; Boller, S.; Wielinga, P.Y.; Schraenen, A.; Lemaire, K.; Debray, S.; Van Lommel, L.; Pospisilik, J.A.; Tschopp, O.; Schultze, S.M.; Malipiero, U.; Esterbauer, H.; Ellingsgaard, H.; Rütti, S.; Schuit, F.C.; Lutz, T.A.; Böni-Schnetzler, M.; Konrad, D.; Donath, M.Y. Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia,  2010, 53(8), 1795-1806.
[http://dx.doi.org/10.1007/s00125-010-1747-3 ] [PMID:  20407745] 
[100] 
Czajka, A.; Ajaz, S.; Gnudi, L.; Parsade, C.K.; Jones, P.; Reid, F.; Malik, A.N. Altered mitochondrial function, mitochondrial DNA and reduced metabolic flexibility in patients with diabetic nephropathy. EBioMedicine,  2015, 2(6), 499-512.
[http://dx.doi.org/10.1016/j.ebiom.2015.04.002 ] [PMID:  26288815] 
[101] 
Tashiro, M.; Sasatomi, Y.; Watanabe, R.; Watanabe, M.; Miyake, K.; Abe, Y.; Yasuno, T.; Ito, K.; Ueki, N.; Hamauchi, A.; Noda, R.; Hisano, S.; Nakashima, H. IL-1β promotes tubulointerstitial injury in MPO-ANCA-associated glomerulonephritis. Clin. Nephrol.,  2016, 86(10), 190-199.
[http://dx.doi.org/10.5414/CN108902 ] [PMID:  27616759] 
[102] 
Wang, H.; Gou, S.J.; Zhao, M.H.; Chen, M. The expression of Toll-like receptors 2, 4 and 9 in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Clin. Exp. Immunol.,  2014, 177(3), 603-610.
[http://dx.doi.org/10.1111/cei.12365 ] [PMID:  24773611] 
[103] 
Lepse, N.; Land, J.; Rutgers, A.; Kallenberg, C.G.; Stegeman, C.A.; Abdulahad, W.H.; Heeringa, P. Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro. Rheumatology (Oxford),  2016, 55(1), 162-172.
[http://dx.doi.org/10.1093/rheumatology/kev293 ] [PMID:  26320128] 
[104] 
Summers, S.A.; van der Veen, B.S.; O’Sullivan, K.M.; Gan, P.Y.; Ooi, J.D.; Heeringa, P.; Satchell, S.C.; Mathieson, P.W.; Saleem, M.A.; Visvanathan, K.; Holdsworth, S.R.; Kitching, A.R. Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. Kidney Int.,  2010, 78(12), 1263-1274.
[http://dx.doi.org/10.1038/ki.2010.327 ] [PMID:  20844472] 
[105] 
Summers, S.A.; Steinmetz, O.M.; Gan, P.Y.; Ooi, J.D.; Odobasic, D.; Kitching, A.R.; Holdsworth, S.R. Toll-like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll-like receptor 9 drives Th1 autoimmunity in murine vasculitis. Arthritis Rheum.,  2011, 63(4), 1124-1135.
[http://dx.doi.org/10.1002/art.30208 ] [PMID:  21190299] 
[106] 
Wang, C.; Chang, D.Y.; Chen, M.; Zhao, M.H. HMGB1 contributes to glomerular endothelial cell injury in ANCA-associated vasculitis through enhancing endothelium-neutrophil interactions. J. Cell. Mol. Med.,  2017, 21(7), 1351-1360.
[http://dx.doi.org/10.1111/jcmm.13065 ] [PMID:  28181422] 
[107] 
Tadema, H.; Abdulahad, W.H.; Lepse, N.; Stegeman, C.A.; Kallenberg, C.G.; Heeringa, P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology (Oxford),  2011, 50(4), 689-696.
[http://dx.doi.org/10.1093/rheumatology/keq375 ] [PMID:  21149241] 
[108] 
Husmann, C.A.; Holle, J.U.; Moosig, F.; Mueller, S.; Wilde, B.; Cohen Tervaert, J.W.; Harper, L.; Assmann, G.; Gross, W.L.; Epplen, J.T.; Wieczorek, S. Genetics of toll like receptor 9 in ANCA associated vasculitides. Ann. Rheum. Dis.,  2014, 73(5), 890-896.
[http://dx.doi.org/10.1136/annrheumdis-2012-202803 ] [PMID:  23592712] 
[109] 
Wu, Z.; Xu, J.; Sun, F.; Chen, H.; Wu, Q.; Zheng, W.; Li, P.; Bai, Y.; Zhang, F.; Li, Y. Single nucleotide polymorphisms in the toll-like receptor 2 (TLR2) gene are associated with microscopic polyangiitis in the northern Han Chinese population. Mod. Rheumatol.,  2015, 25(2), 224-229.
[http://dx.doi.org/10.3109/14397595.2014.950034 ] [PMID:  25180613] 
[110] 
Zheng, S.; Pan, Y.; Wang, C.; Liu, Y.; Shi, M.; Ding, G. HMGB1 turns renal tubular epithelial cells into inflammatory promoters by interacting with TLR4 during sepsis. J. Interferon Cytokine Res.,  2016, 36(1), 9-19.
[http://dx.doi.org/10.1089/jir.2015.0067 ] [PMID:  26312770] 
[111] 
Matejovic, M.; Valesova, L.; Benes, J.; Sykora, R.; Hrstka, R.; Chvojka, J. Molecular differences in susceptibility of the kidney to sepsis-induced kidney injury. BMC Nephrol.,  2017, 18(1), 183.
[http://dx.doi.org/10.1186/s12882-017-0602-x ] [PMID:  28569136] 
[112] 
Allam, R.; Scherbaum, C.R.; Darisipudi, M.N.; Mulay, S.R.; Hägele, H.; Lichtnekert, J.; Hagemann, J.H.; Rupanagudi, K.V.; Ryu, M.; Schwarzenberger, C.; Hohenstein, B.; Hugo, C.; Uhl, B.; Reichel, C.A.; Krombach, F.; Monestier, M.; Liapis, H.; Moreth, K.; Schaefer, L.; Anders, H.J. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol.,  2012, 23(8), 1375-1388.
[http://dx.doi.org/10.1681/ASN.2011111077 ] [PMID:  22677551] 
[113] 
Van Beusecum, J.P.; Zhang, S.; Cook, A.K.; Inscho, E.W. Acute toll-like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour. Acta Physiol. (Oxf.),  2017, 221(3), 204-220.
[http://dx.doi.org/10.1111/apha.12899 ] [PMID:  28544543] 
[114] 
Tsuji, N.; Tsuji, T.; Ohashi, N.; Kato, A.; Fujigaki, Y.; Yasuda, H. Role of mitochondrial DNA in septic AKI via toll-like receptor 9. J. Am. Soc. Nephrol.,  2016, 27(7), 2009-2020.
[http://dx.doi.org/10.1681/ASN.2015040376 ] [PMID:  26574043] 
[115] 
Deng, M.; Scott, M.J.; Loughran, P.; Gibson, G.; Sodhi, C.; Watkins, S. Lipopolysaccharide clearance, bacterial clearance, and sys-temic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J. Immunol.,  2013, 190(10), 5152-5160.
[http://dx.doi.org/10.4049/jimmunol.1300496 ] [PMID:  23562812] 
[116] 
Good, D.W.; George, T.; Watts, B.A. III Toll-like receptor 2 is required for LPS-induced Toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J. Biol. Chem.,  2012, 287(24), 20208-20220.
[http://dx.doi.org/10.1074/jbc.M111.336255 ] [PMID:  22523073] 
[117] 
Yang, L.; Xie, M.; Yang, M.; Yu, Y.; Zhu, S.; Hou, W.; Kang, R.; Lotze, M.T.; Billiar, T.R.; Wang, H.; Cao, L.; Tang, D. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat. Commun.,  2014, 5, 4436.
[http://dx.doi.org/10.1038/ncomms5436 ] [PMID:  25019241] 
[118] 
Mansur, A.; von Gruben, L.; Popov, A.F.; Steinau, M.; Bergmann, I.; Ross, D.; Ghadimi, M.; Beissbarth, T.; Bauer, M.; Hinz, J. The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients. J. Transl. Med.,  2014, 12, 177.
[http://dx.doi.org/10.1186/1479-5876-12-177 ] [PMID:  24950711] 
[119] 
Anderberg, S.B.; Luther, T.; Frithiof, R. Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury. Acta Physiol. (Oxf.),  2017, 219(3), 573-588.
[http://dx.doi.org/10.1111/apha.12798 ] [PMID:  27602552] 
[120] 
Castoldi, A.; Braga, T.T.; Correa-Costa, M.; Aguiar, C.F.; Bassi, E.J.; Correa-Silva, R.; Elias, R.M.; Salvador, F.; Moraes-Vieira, P.M.; Cenedeze, M.A.; Reis, M.A.; Hiyane, M.I.; Pacheco-Silva, Á.; Gonçalves, G.M.; Saraiva Câmara, N.O. TLR2, TLR4 and the MYD88 signaling pathway are crucial for neutrophil migration in acute kidney injury induced by sepsis. PLoS One,  2012, 7(5),e37584.
[http://dx.doi.org/10.1371/journal.pone.0037584 ] [PMID:  22655058] 
[121] 
Liu, J.; Li, G.; Xie, W.J.; Wang, L.; Zhang, R.; Huang, K.S.; Zhou, Q.S.; Chen, D.C. Lipopolysaccharide stimulates surfactant protein-A in human renal epithelial HK-2 cells through upregulating toll-like receptor 4 dependent MEK1/2-ERK1/2-NF-κB pathway. Chin. Med. J. (Engl.),  2017, 130(10), 1236-1243.
[http://dx.doi.org/10.4103/0366-6999.205853 ] [PMID:  28485325] 
[122] 
Kulkarni, O.P.; Hartter, I.; Mulay, S.R.; Hagemann, J.; Darisipudi, M.N.; Kumar Vr, S.; Romoli, S.; Thomasova, D.; Ryu, M.; Kobold, S.; Anders, H.J. Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J. Am. Soc. Nephrol.,  2014, 25(5), 978-989.
[http://dx.doi.org/10.1681/ASN.2013050528 ] [PMID:  24459235] 
[123] 
Zou, L.; Feng, Y.; Li, Y.; Zhang, M.; Chen, C.; Cai, J. Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sep-sis. J. Immunol.,  2013, 191(11), 5625-5635.
[http://dx.doi.org/10.4049/jimmunol.1301903 ] [PMID:  24154627] 
[124] 
Lee, I.T.; Shih, R.H.; Lin, C.C.; Chen, J.T.; Yang, C.M. Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells. Cell Commun. Signal.,  2012, 10(1), 33.
[http://dx.doi.org/10.1186/1478-811X-10-33 ] [PMID:  23153039] 
[125] 
Zhang, M.; Zou, L.; Feng, Y.; Chen, Y.J.; Zhou, Q.; Ichinose, F.; Chao, W. Toll-like receptor 4 is essential to preserving cardiac function and survival in low-grade polymicrobial sepsis. Anesthesiology,  2014, 121(6), 1270-1280.
[http://dx.doi.org/10.1097/ALN.0000000000000337 ] [PMID:  24937074] 
[126] 
Vallés, P.G.; Lorenzo, A.G.; Bocanegra, V.; Vallés, R. Acute kidney injury: what part do toll-like receptors play? Int. J. Nephrol. Renovasc. Dis.,  2014, 7, 241-251.
[http://dx.doi.org/10.2147/IJNRD.S37891 ] [PMID:  24971030] 
[127] 
Leemans, J.C.; Stokman, G.; Claessen, N.; Rouschop, K.M.; Teske, G.J.; Kirschning, C.J.; Akira, S.; van der Poll, T.; Weening, J.J.; Florquin, S. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest.,  2005, 115(10), 2894-2903.
[http://dx.doi.org/10.1172/JCI22832 ] [PMID:  16167081] 
[128] 
Urbschat, A.; Baer, P.; Zacharowski, K.; Sprunck, V.; Scheller, B.; Raimann, F.; Maier, T.J.; Hegele, A.; Hofmann, R.; Mersmann, J. Systemic TLR2 antibody application in renal ischaemia and reperfusion injury decreases AKT phosphorylation and increases apoptosis in the mouse kidney. Basic Clin. Pharmacol. Toxicol.,  2018, 122(2), 223-232.
[http://dx.doi.org/10.1111/bcpt.12896 ] [PMID:  28857508] 
[129] 
Amura, C.R.; Renner, B.; Lyubchenko, T.; Faubel, S.; Simonian, P.L.; Thurman, J.M. Complement activation and toll-like receptor-2 signaling contribute to cytokine production after renal ischemia/reperfusion. Mol. Immunol.,  2012, 52(3-4), 249-257.
[http://dx.doi.org/10.1016/j.molimm.2012.05.020 ] [PMID:  22750071] 
[130] 
Chen, J.; John, R.; Richardson, J.A.; Shelton, J.M.; Zhou, X.J.; Wang, Y.; Wu, Q.Q.; Hartono, J.R.; Winterberg, P.D.; Lu, C.Y. Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. Kidney Int.,  2011, 79(3), 288-299.
[http://dx.doi.org/10.1038/ki.2010.381 ] [PMID:  20927041] 
[131] 
Dagher, P.C.; Hato, T.; Mang, H.E.; Plotkin, Z.; Richardson, Q.V.; Massad, M.; Mai, E.; Kuehl, S.E.; Graham, P.; Kumar, R.; Sutton, T.A. Inhibition of toll-like receptor 4 signaling mitigates microvascular loss but not fibrosis in a model of ischemic acute kidney injury. Int. J. Mol. Sci.,  2016, 17(5),E647.
[http://dx.doi.org/10.3390/ijms17050647 ] [PMID:  27136544] 
[132] 
Paulus, P.; Rupprecht, K.; Baer, P.; Obermüller, N.; Penzkofer, D.; Reissig, C.; Scheller, B.; Holfeld, J.; Zacharowski, K.; Dimmeler, S.; Schlammes, J.; Urbschat, A. The early activation of toll-like receptor (TLR)-3 initiates kidney injury after ischemia and reperfusion. PLoS One,  2014, 9(4),e94366.
[http://dx.doi.org/10.1371/journal.pone.0094366 ] [PMID:  24736450] 
[133] 
Yayi, H.; Yeda, X.; Huaxin, W.; Yang, W.; Qian, S.; Zhongyuan, X. Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats. Acta Cir. Bras.,  2016, 31(7), 448-455.
[http://dx.doi.org/10.1590/S0102-865020160070000004 ] [PMID:  27487279] 
[134] 
Gluba, A.; Banach, M.; Hannam, S.; Mikhailidis, D.P.; Sakowicz, A.; Rysz, J. The role of Toll-like receptors in renal diseases. Nat. Rev. Nephrol.,  2010, 6(4), 224-235.
[http://dx.doi.org/10.1038/nrneph.2010.16 ] [PMID:  20177402] 
[135] 
Ma, X.; Yan, L.; Zhu, Q.; Shao, F. Puerarin attenuates cisplatin-induced rat nephrotoxicity: The involvement of TLR4/NF-κB signaling pathway. PLoS One,  2017, 12(2),e0171612.
[http://dx.doi.org/10.1371/journal.pone.0171612 ] [PMID:  28182789] 
[136] 
Andrade-Silva, M.; Cenedeze, M.A.; Perandini, L.A.; Feliz-ardo, R.J.F.; Watanabe, I.M.; Agudelo, J.S.H. TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury. Clin. Sci. ,  2018, 132(16), 1725-1739.
[http://dx.doi.org/10.1042/CS20170262 ] [PMID:  29500224] 
[137] 
Alikhan, M.A.; Summers, S.A.; Gan, P.Y.; Chan, A.J.; Khouri, M.B.; Ooi, J.D.; Ghali, J.R.; Odobasic, D.; Hickey, M.J.; Kitching, A.R.; Holdsworth, S.R. Endogenous toll-like receptor 9 regulates AKI by promoting regulatory T cell recruitment. J. Am. Soc. Nephrol.,  2016, 27(3), 706-714.
[http://dx.doi.org/10.1681/ASN.2014090927 ] [PMID:  26116356] 
[138] 
Ali, F.; Dua, A.; Cronin, D.C. Changing paradigms in organ preservation and resuscitation. Curr. Opin. Organ Transplant.,  2015, 20(2), 152-158.
[http://dx.doi.org/10.1097/MOT.0000000000000180 ] [PMID:  25719899] 
[139] 
Krüger, B.; Krick, S.; Dhillon, N.; Lerner, S.M.; Ames, S.; Bromberg, J.S.; Lin, M.; Walsh, L.; Vella, J.; Fischereder, M.; Krämer, B.K.; Colvin, R.B.; Heeger, P.S.; Murphy, B.T.; Schröppel, B. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc. Natl. Acad. Sci. USA,  2009, 106(9), 3390-3395.
[http://dx.doi.org/10.1073/pnas.0810169106 ] [PMID:  19218437] 
[140] 
Thierry, A.; Giraud, S.; Robin, A.; Barra, A.; Bridoux, F.; Ameteau, V.; Hauet, T.; Girard, J.P.; Touchard, G.; Gombert, J.M.; Herbelin, A. The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33. PLoS One,  2014, 9(2)e88742
[http://dx.doi.org/10.1371/journal.pone.0088742 ] [PMID:  24586382] 
[141] 
Kono, H.; Chen, C.J.; Ontiveros, F.; Rock, K.L. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J. Clin. Invest.,  2010, 120(6), 1939-1949.
[http://dx.doi.org/10.1172/JCI40124 ] [PMID:  20501947] 
[142] 
Scheibner, K.A.; Lutz, M.A.; Boodoo, S.; Fenton, M.J.; Powell, J.D.; Horton, M.R. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol.,  2006, 177(2), 1272-1281.
[http://dx.doi.org/10.4049/jimmunol.177.2.1272 ] [PMID:  16818787] 
[143] 
Kwan, T.K.; Chadban, S.J.; Wu, H. Toll-like receptor 4 deficiency improves short-term renal function but not long-term graft survival in a fully MHC-mismatched murine model of renal allograft transplantation. Transplantation,  2016, 100(6), 1219-1227.
[http://dx.doi.org/10.1097/TP.0000000000001168 ] [PMID:  27077596] 
[144] 
Yang, J.; Snijders, M.L.H.; Haasnoot, G.W.; van Kooten, C.; Mallat, M.; de Fijter, J.W.; Clahsen-van Groningen, M.C.; Claas, F.H.J.; Eikmans, M. Elevated intragraft expression of innate immunity and cell death-related markers is a risk factor for adverse graft outcome. Transpl. Immunol.,  2018, 48, 39-46.
[http://dx.doi.org/10.1016/j.trim.2018.02.009 ] [PMID:  29475090] 
[145] 
Hosseinzadeh, M.; Ahmadpoor, P.; Yekaninejad, M.S.; Pourrezagholi, F.; Foroughi, F.; Ghorbanpour, M.; Barabadi, M.; Shahbaz, S.K.; Solgi, G.; Amirzargar, A. Expression patterns of Toll like receptor (TLR)-2, TLR-4 and myeloid differentiation primary response gene 88 (MYD88) in renal transplant patients developing allograft dysfunction; a cohort study. Transpl. Immunol.,  2018, 48, 26-31.
[http://dx.doi.org/10.1016/j.trim.2018.02.005 ] [PMID:  29452169] 
[146] 
Wang, S.; Schmaderer, C.; Kiss, E.; Schmidt, C.; Bonrouhi, M.; Porubsky, S.; Gretz, N.; Schaefer, L.; Kirschning, C.J.; Popovic, Z.V.; Gröne, H.J. Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis. Model. Mech.,  2010, 3(1-2), 92-103.
[http://dx.doi.org/10.1242/dmm.003533 ] [PMID:  20038715] 
[147] 
Wu, H.; Chen, G.; Wyburn, K.R.; Yin, J.; Bertolino, P.; Eris, J.M.; Alexander, S.I.; Sharland, A.F.; Chadban, S.J. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest.,  2007, 117(10), 2847-2859.
[http://dx.doi.org/10.1172/JCI31008 ] [PMID:  17853945] 
[148] 
Cucchiari, D.; Podestà, M.A.; Ponticelli, C. The critical role of innate immunity in kidney transplantation. Nephron,  2016, 132(3), 227-237.
[http://dx.doi.org/10.1159/000444267 ] [PMID:  26914915] 
[149] 
Pittman, K.; Kubes, P. Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun.,  2013, 5(4), 315-323.
[http://dx.doi.org/10.1159/000347132 ] [PMID:  23486162] 
[150] 
de Groot, K.; Kuklik, K.; Bröcker, V.; Schwarz, A.; Gwinner, W.; Kreipe, H.; Haller, H.; Fliser, D.; Mengel, M. Toll-like receptor 2 and renal allograft function. Am. J. Nephrol.,  2008, 28(4), 583-588.
[http://dx.doi.org/10.1159/000115974 ] [PMID:  18264007] 
[151] 
Zhuang, Q.; Lakkis, F.G. Dendritic cells and innate immunity in kidney transplantation. Kidney Int.,  2015, 87(4), 712-718.
[http://dx.doi.org/10.1038/ki.2014.430 ] [PMID:  25629552] 
[152] 
Dessing, M.C.; Kers, J.; Damman, J.; Leuvenink, H.G.D.; van Goor, H.; Hillebrands, J.L.; Hepkema, B.G.; Snieder, H.; van den Born, J.; de Borst, M.H.; Bakker, S.J.; Navis, G.J.; Ploeg, R.J.; Florquin, S.; Seelen, M.; Leemans, J.C. Toll-like receptor family polymorphisms are associated with primary renal diseases but not with renal outcomes following kidney transplantation. PLoS One,  2015, 10(10),e0139769.
[http://dx.doi.org/10.1371/journal.pone.0139769 ] [PMID:  26445497] 
[153] 
Kim, J.S.; Kim, S.K.; Park, J.Y.; Kim, Y.G.; Moon, J.Y.; Lee, S.H.; Ihm, C.G.; Lee, T.W.; Kim, S.K.; Chung, J.H.; Kang, S.W.; Kim, T.H.; Kim, Y.H.; Jeong, K.H. Significant association between toll-like receptor gene polymorphisms and posttransplantation diabetes mellitus. Nephron,  2016, 133(4), 279-286.
[http://dx.doi.org/10.1159/000446570 ] [PMID:  27486667] 
[154] 
Bergallo, M.; Montanari, P.; Mareschi, K.; Rassu, M.; Galliano, I.; Ravanini, P. A novel TaqMAMA assay for allelic discrimination of TLR9 rs352140 polymorphism. J. Virol. Methods,  2017, 243, 25-30.
[http://dx.doi.org/10.1016/j.jviromet.2017.01.015 ] [PMID:  28143777] 
[155] 
Braza, F.; Brouard, S.; Chadban, S.; Goldstein, D.R. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat. Rev. Nephrol.,  2016, 12(5), 281-290.
[http://dx.doi.org/10.1038/nrneph.2016.41 ] [PMID:  27026348] 
[156] 
Stafford, S.L.; Bokil, N.J.; Achard, M.E.; Kapetanovic, R.; Schembri, M.A.; McEwan, A.G.; Sweet, M.J. Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci. Rep.,  2013, 33(4),e00049.
[http://dx.doi.org/10.1042/BSR20130014 ] [PMID:  23738776] 
[157] 
Shih, C.T.; Shiu, Y.L.; Chen, C.A.; Lin, H.Y.; Huang, Y.L.; Lin, C.C. Changes in levels of copper, iron, zinc, and selenium in patients at different stages of chronic kidney disease. Genom. Med. Biom. Heal. Sci.,  2012, 4(4), 128-130.
[http://dx.doi.org/10.1016/j.gmbhs.2013.03.001] 
[158] 
Kung, W.J.; Shih, C.T.; Lee, C.H.; Lin, C.C. The divalent elements changes in early stages of chronic kidney disease. Biol. Trace Elem. Res.,  2018, 185(1), 30-35.
[http://dx.doi.org/10.1007/s12011-017-1228-3 ] [PMID:  29285723] 
[159] 
Roh, Y.S.; Seki, E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J. Gastroenterol. Hepatol.,  2013, 28(Suppl. 1), 38-42.
[http://dx.doi.org/10.1111/jgh.12019 ] [PMID:  23855294] 
[160] 
Tarantino, G.; Porcu, C.; Arciello, M.; Andreozzi, P.; Balsano, C. Prediction of carotid intima-media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability. J. Gastroenterol. Hepatol.,  2018, 33(8), 1511-1517.
[http://dx.doi.org/10.1111/jgh.14104 ] [PMID:  29405466] 
[161] 
Skuginna, V.; Lech, M.; Allam, R.; Ryu, M.; Clauss, S.; Susanti, H.E.; Römmele, C.; Garlanda, C.; Mantovani, A.; Anders, H.J. Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction. PLoS One,  2011, 6(4),e19204.
[http://dx.doi.org/10.1371/journal.pone.0019204 ] [PMID:  21544241] 
[162] 
Anders, H.J.; Schaefer, L. Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J. Am. Soc. Nephrol.,  2014, 25(7), 1387-1400.
[http://dx.doi.org/10.1681/ASN.2014010117 ] [PMID:  24762401] 
[163] 
Yiu, W.H.; Lin, M.; Tang, S.C.W. Toll-like receptor activation: from renal inflammation to fibrosis. Kidney Int. Suppl.,  2014, 4(1), 20-25.
[http://dx.doi.org/10.1038/kisup.2014.5 ] [PMID:  26312146] 
[164] 
Braga, T.T.; Correa-Costa, M.; Guise, Y.F.; Castoldi, A.; de Oliveira, C.D.; Hyane, M.I.; Cenedeze, M.A.; Teixeira, S.A.; Muscara, M.N.; Perez, K.R.; Cuccovia, I.M.; Pacheco-Silva, A.; Gonçalves, G.M.; Camara, N.O. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages. Mol. Med.,  2012, 18, 1231-1239.
[http://dx.doi.org/10.2119/molmed.2012.00131 ] [PMID:  22777483] 
[165] 
Nakagawa, S. Identification of biomarkers for tubular injury and interstitial fibrosis in chronic kidney disease Yakugaku Zasshi,  2017, 137(11), 1355-1360.
[http://dx.doi.org/10.1248/yakushi.17-00150 ] [PMID:  29093371] 
[166] 
Leemans, J.C.; Butter, L.M.; Pulskens, W.P.; Teske, G.J.; Claessen, N.; van der Poll, T.; Florquin, S. The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury. PLoS One,  2009, 4(5),e5704.
[http://dx.doi.org/10.1371/journal.pone.0005704 ] [PMID:  19479087] 
[167] 
Pulskens, W.P.; Rampanelli, E.; Teske, G.J.; Butter, L.M.; Claessen, N.; Luirink, I.K.; van der Poll, T.; Florquin, S.; Leemans, J.C. TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury. J. Am. Soc. Nephrol.,  2010, 21(8), 1299-1308.
[http://dx.doi.org/10.1681/ASN.2009070722 ] [PMID:  20595685] 
[168] 
Kim, H.W.; Woo, Y.S.; Yang, H.N.; Choi, H.M.; Jo, S.K.; Cho, W.Y.; Kim, H.K. Primed monocytes: putative culprits of chronic low-grade inflammation and impaired innate immune responses in patients on hemodialysis. Clin. Exp. Nephrol.,  2011, 15(2), 258-263.
[http://dx.doi.org/10.1007/s10157-010-0379-8 ] [PMID:  21152946] 
[169] 
Kim, K.I.; Jeong, S.; Han, N.; Oh, J.M.; Oh, K.H.; Kim, I.W. Identification of differentially expressed miRNAs associated with chronic kidney disease-mineral bone disorder. Front. Med.,  2017, 11(3), 378-385.
[http://dx.doi.org/10.1007/s11684-017-0541-8 ] [PMID:  28623542] 
[170] 
Koc, M.; Toprak, A.; Arikan, H.; Odabasi, Z.; Elbir, Y.; Tulunay, A.; Asicioglu, E.; Eksioglu-Demiralp, E.; Glorieux, G.; Vanholder, R.; Akoglu, E. Toll-like receptor expression in monocytes in patients with chronic kidney disease and haemodialysis: relation with inflammation. Nephrol. Dial. Transplant.,  2011, 26(3), 955-963.
[http://dx.doi.org/10.1093/ndt/gfq500 ] [PMID:  20729266] 
[171] 
Speer, T.; Rohrer, L.; Blyszczuk, P.; Shroff, R.; Kuschnerus, K.; Kränkel, N.; Kania, G.; Zewinger, S.; Akhmedov, A.; Shi, Y.; Martin, T.; Perisa, D.; Winnik, S.; Müller, M.F.; Sester, U.; Wernicke, G.; Jung, A.; Gutteck, U.; Eriksson, U.; Geisel, J.; Deanfield, J.; von Eckardstein, A.; Lüscher, T.F.; Fliser, D.; Bahlmann, F.H.; Landmesser, U. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity,  2013, 38(4), 754-768.
[http://dx.doi.org/10.1016/j.immuni.2013.02.009 ] [PMID:  23477738] 
[172] 
Kong, X.; Sun, J.; Cui, M.; Xu, D. The serum from dialysis patients with acute coronary syndrome up-regulates the expression of TLR2 and its downstream effectors in human renal glomerular endothelial cells. Ren. Fail.,  2014, 36(5), 785-789.
[http://dx.doi.org/10.3109/0886022X.2014.886466 ] [PMID:  24524679] 
[173] 
Yang, H.Y.; Huang, S.M.; Lu, K.C.; Wu, C.C.; Kang, C.Y.; Lin, Y.F.; Lin, C.; Lin, F.H.; Kao, S.Y.; Su, S.L. A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease. Am. J. Nephrol.,  2014, 40(2), 131-139.
[http://dx.doi.org/10.1159/000365934 ] [PMID:  25171218] 
[174] 
Singh, K.; Prasad, K.N.; Mishra, P.; Khatoon, J.; Prasad, N.; Gupta, A.; Srivastava, J.K. Toll-like receptors TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) gene polymorphisms in end-stage renal disease patients on peritoneal dialysis. Int. Urol. Nephrol.,  2015, 47(12), 2031-2037.
[http://dx.doi.org/10.1007/s11255-015-1124-8 ] [PMID:  26490558] 
[175] 
Ashkar, A.A.; Mossman, K.L.; Coombes, B.K.; Gyles, C.L.; Mackenzie, R. FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which re-quires TLR4 and type 1 interferon signaling. PLoS pathogens.,  2008, 4(12),e1000233.
[http://dx.doi.org/10.1371/journal.ppat.1000233 ] [PMID:  19057665] 
[176] 
Schilling, J.D.; Martin, S.M.; Hunstad, D.A.; Patel, K.P.; Mulvey, M.A.; Justice, S.S.; Lorenz, R.G.; Hultgren, S.J. CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by lipo-polysaccharide and type 1 piliated Escherichia coli. Infect. Immun.,  2003, 71(3), 1470-1480.
[http://dx.doi.org/10.1128/iai.71.3.1470-1480.2003 ] [PMID:  12595465] 
[177] 
Song, J.; Duncan, M.J.; Li, G.; Chan, C.; Grady, R.; Stapleton, A.; Abraham, S.N. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog.,  2007, 3(4),e60.
[http://dx.doi.org/10.1371/journal.ppat.0030060 ] [PMID:  17465679] 
[178] 
Backhed, F.; Soderhall, M.; Ekman, P.; Normark, S.; Richter-Dahlfors, A. Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract. Cell. Microbiol.,  2001, 3(3), 153-158.
[http://dx.doi.org/10.1046/j.1462-5822.2001.00101.x ] [PMID:  11260138] 
[179] 
McCarthy, D.D.; Chiu, S.; Gao, Y.; Summers-deLuca, L.E.; Gommerman, J.L. BAFF induces a hyper-IgA syndrome in the intestinal lamina propria concomitant with IgA deposition in the kidney independent of LIGHT. Cell. Immunol.,  2006, 241(2), 85-94.
[http://dx.doi.org/10.1016/j.cellimm.2006.08.002 ] [PMID:  16987502] 
[180] 
Lim, B.J.; Lee, D.; Hong, S.W.; Jeong, H.J. Toll-like receptor 4 signaling is involved in IgA-stimulated mesangial cell activation. Yonsei Med. J.,  2011, 52(4), 610-615.
[http://dx.doi.org/10.3349/ymj.2011.52.4.610 ] [PMID:  21623603] 
[181] 
Banas, M.C.; Banas, B.; Hudkins, K.L.; Wietecha, T.A.; Iyoda, M.; Bock, E.; Hauser, P.; Pippin, J.W.; Shankland, S.J.; Smith, K.D.; Stoelcker, B.; Liu, G.; Gröne, H-J.; Krämer, B.K.; Alpers, C.E. TLR4 links podocytes with the innate immune system to mediate glomerular injury. J. Am. Soc. Nephrol.,  2008, 19(4), 704-713.
[http://dx.doi.org/10.1681/ASN.2007040395 ] [PMID:  18256364] 
[182] 
Souyris, M.; Cenac, C.; Azar, P.; Daviaud, D.; Canivet, A.; Grunenwald, S.; Pienkowski, C.; Chaumeil, J.; Mejía, J.E.; Guéry, J-C. 5 TLR7 escapes X chromosome inac-tivation in immune cells. Sci. Immunol.,  2018, 3(19),eaap8855.
[http://dx.doi.org/10.1126/sciimmunol.aap8855 ] [PMID:  29374079] 
[183] 
Sawa, Y.; Takata, S.; Hatakeyama, Y.; Ishikawa, H.; Tsuruga, E. Expression of toll-like receptor 2 in glomerular endothelial cells and promotion of diabetic nephropathy by porphyromonas gingivalis lipopolysaccharide. PLoS One,  2014, 9(5),e97165.
[http://dx.doi.org/10.1371/journal.pone.0097165 ] [PMID:  24835775] 
[184] 
Moreth, K.; Frey, H.; Hubo, M.; Zeng-Brouwers, J.; Nastase, M.V.; Hsieh, L.T.H.; Haceni, R.; Pfeilschifter, J. Iozzo, R.V.; Schaefer, L. Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of is-chemic acute kidney injury. Matrix Biol.,  2014, 35, 143-151.
[http://dx.doi.org/10.1016/j.matbio.2014.01.010 ] [PMID:  24480070] 
[185] 
Arbour, N.C.; Lorenz, E.; Schutte, B.C.; Zabner, J.; Kline, J.N.; Jones, M.; Frees, K.; Watt, J.L.; Schwartz, D.A. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet.,  2000, 25(2), 187-191.
[http://dx.doi.org/10.1038/76048 ] [PMID:  10835634] 
[186] 
Cunningham, P.N.; Wang, Y.; Guo, R.; He, G.; Quigg, R.J. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol.,  2004, 172(4), 2629-2635.
[http://dx.doi.org/10.4049/jimmunol.172.4.2629 ] [PMID:  14764737] 
[187] 
Hosseinzadeh, M.; Nafar, M.; Ahmadpoor, P.; Noorbakhsh, F.; Yekaninejad, M.S.; Niknam, M.H.; Amirzargar, A. Increased expression of toll-like receptors 2 and 4 in renal trans-plant recipients that develop allograft dysfunction: a cohort study. Iran. J. Immunol.,  2017, 14(1), 24-34.
[PMID:  28341816] 
[188] 
Yang, H.Y.; Lu, K.C.; Lee, H.S.; Huang, S.M.; Lin, Y.F.; Wu, C.C.; Salter, D.M.; Su, S-L. Role of the functional Toll-Like receptor-9 promot-er polymorphism (-1237T/C) in increased risk of end-stage renal disease: a case-control study. PloS one,  2013, 8(3),e58444.
[http://dx.doi.org/10.1371/journal.pone.0058444 ] [PMID:  23472199] 
[189] 
Lu, K.C.; Yang, H.Y.; Lin, Y.F.; Kao, S.Y.; Lai, C.H.; Chu, C.M.; Wu, C-C.; Su, S-L. The T-1237C polymorphism of the Toll-like receptor-9 gene is associated with chronic kidney disease in a Han Chinese population. Tohoku J Exp. Med.,  2011, 225(2), 109-116.
[http://dx.doi.org/10.1620/tjem.225.109 ] [PMID:  21908957] 
Cite As
Current Medicinal Chemistry

Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases

Abstract
