Abstract
Introduction: Renal ischemia/reperfusion (IR) is a major cause of acute kidney injury (AKI). The benefit of novel non-steroidal MR antagonists such as finerenone in the IR context has not been evaluated and the mechanisms underlying the benefit of MR antagonism remain unclear. Objectives: To test the efficacy of finerenone in ischemic AKI and to evaluate the specific contribution of the MR expressed in endothelial or smooth muscle cell (SMC) in renal IR injury. Methods: We included 18 male C57/B6 mice that were divided in: sham, renal ischemia for 20 min and IR plus treatment with finerenone (10 mg/kg) by gavage once a day at -48, -24 and -1 h before IR. Alternatively, MR inactivation in endothelial cells (MR endoKO mice /Vecadh-cre) or in smooth muscle cells (MR SMCKO mice/SMA-cre) was induced in 3-month-old mice. Sham surgery or bilateral renal IR for 20 min was performed and mice were studied 24 h after reperfusion. Primary rat SMC cultures were used to assess the signaling pathways modulated by MR. Results: In C57/B6 WT, MR fl/fl and MR endoKO mice, IR induced kidney dysfunction and tubular injury. After IR, Finerenone-treated mice and the MR SMCKO mice presented normal renal function and a significant reduction of histological alterations, while MR endoKO mice were not protected. The benefit of finerenone and MR KO in SMC was associated with reduced oxidative stress-mediated lipid peroxidation as compared to MR fl/fl or WT mice. In aldosterone-stimulated rat SMC, we observed a 100% increase in hydrogen peroxide production and a 2-fold increase in Rac1 activity; MR and Rac1 antagonism blunted these effects. Moreover, mice deficient of Rac1 in SMC were also protected against ischemic AKI. Conclusion: Finerenone limits renal injury induced by IR. Moreover, genetic deletion of MR in SMC only has similar effects. This benefit was associated with reduced oxidative stress, by affecting oxidative stress production via SMC Rac1.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.