Escola Paulista de Medicina
Programa de Postgrado en Nefrología

TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury

ppclinsci 132 12and13 cover

Authors: Magaiver Andrade-SilvaMarcos Antonio CenedezeLuiz Augusto PerandiniRaphael José Ferreira FelizardoIngrid Kazue Mizuno WatanabeJuan Sebastian Henao AgudeloAngela CastoldiGiselle Martins GonçalvesClarice Silvia Taemi OrigassaPatricia SemedoMeire Ioshie HiyaneOrestes Foresto-NetoDenise Maria Avancini Costa MalheirosMarlene Antonia ReisClarice Kazue FujiharaRoberto ZatzAlvaro Pacheco-SilvaNiels Olsen Saraiva CâmaraDanilo Candido de Almeida.


Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.

DOI: 10.1042/CS20170262



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