TLR۴‐IN‐C۳۴ protects against acute kidney injury via modulating TLR۴/MyD۸۸/NF-κb axis, MAPK, and apoptosis

Objective(s): Acute kidney injury (AKI) is a major component of isoproterenol (ISO) induced cardiorenal syndrome. In this study, we investigated the effect of TLR۴‐IN‐C۳۴ as a toll-like receptor (TLR)-۴ inhibitor on ameliorating ISO-induced AKI and the possible molecular underlying pathways. Materials and Methods: The study included ۴ groups: control group, ISO group (rats received ۱۰۰ mg/kg ISO in ۲ doses ۲۴ hr apart, SC), ISO+C۳۴۱ and ISO+C۳۴۳ groups (rats received ۱ or ۳ mg/kg TLR۴‐IN‐C۳۴ respectively twice one hour before each ISO injection, IP). Results: Obtained results showed that TLR۴‐IN‐C۳۴ injection prior to ISO decreased serum creatinine level (P<۰.۰۵). Renal tissue histopathologic changes were markedly decreased by TLR۴‐IN‐C۳۴. Renal relative expression of MAPK and MyD۸۸ mRNA decreased significantly in both ISO+C۳۴۱ and ISO+C۳۴۳ groups compared with the ISO group (P<۰.۰۵). Furthermore, TLR-IN-C۳۴ lowered the inflammatory cytokines IL-۸, IL-۱β, and IL-۱۲ renal levels (P<۰.۰۵). Immunostained kidney sections showed a marked decrease in NF-κb positive cells in addition to the apoptotic marker Bax (P<۰.۰۵) by the two tested doses of TLR۴‐IN‐C۳۴. On the other hand, the expression of the antiapoptotic marker Bcl-۲ by renal cells was markedly increased. Conclusion: It can be concluded that TLR۴-IN-C۳۴ ameliorates ISO-induced AKI through anti-inflammatory anti-apoptotic effects and modulation of TLR۴ signaling pathways.

Keywords:

Apoptosis , Isoproterenol , MAPK , MyD۸۸ , NF-kappa B , Toll-Like Receptor