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TLR4-mediated inflammation is a key pathogenic event leading to kidney damage and fibrosis in cyclosporine nephrotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

Cyclosporine A (CsA) successfully prevents allograft rejection, but nephrotoxicity is still a dose-limiting adverse effect. TLR4 activation promotes kidney damage but whether this innate immunity receptor mediates CsA nephrotoxicity is unknown. The in vivo role of TLR4 during CsA nephrotoxicity was studied in mice co-treated with CsA and the TLR4 inhibitor TAK242 and also in TLR4−/− mice. CsA-induced renal TLR4 expression in wild-type mice. Pharmacological or genetic targeting of TLR4 reduced the activation of proinflammatory signaling, including JNK/c-jun, JAK2/STAT3, IRE1α and NF-κB and the expression of Fn14. Expression of proinflammatory factors and cytokines was also decreased, and kidney monocyte and lymphocyte influx was prevented. TLR4 inhibition also reduced tubular damage and drastically prevented the development of kidney fibrosis. In vivo and in vitro CsA promoted secretion of the TLR ligand HMGB1 by tubular cells upstream of TLR4 activation, and prevention of HMGB1 secretion significantly reduced CsA-induced synthesis of MCP-1, suggesting that HMGB1 may be one of the mediators of CsA-induced TLR4 activation. These results suggest that TLR4 is a potential pharmacological target in CsA nephrotoxicity.

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Acknowledgments

This work was supported by grants from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, Gobierno de España): FEDER funds ISCIII RETIC REDINREN RD12/0021, PI11/02242, PI13/00047, PI14/00386, PI15/01460; Consejería de Sanidad, Comunidad de Madrid (CIFRA S2010/BMD-2378); Sociedad Española de Nefrología. Salary support: REDINREN to CG-G; Universidad Autónoma de Madrid to JE; Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO; Contrato Miguel Servet (ISCIII) to AMR.

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Correspondence to Adrián M. Ramos.

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González-Guerrero, C., Cannata-Ortiz, P., Guerri, C. et al. TLR4-mediated inflammation is a key pathogenic event leading to kidney damage and fibrosis in cyclosporine nephrotoxicity. Arch Toxicol 91, 1925–1939 (2017). https://doi.org/10.1007/s00204-016-1830-8

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