Activation of Mas and pGCA receptor pathways protects renal epithelial cell damage against oxidative-stress-induced...

Over-activation of the renin-angiotensin-aldosterone system (RAAS) is a leading cause of cardio-renal complications. Oxidative stress is one of the major contributing factors in the over-activation of RAAS. Angiotensin-converting enzyme2/Angiotensin1-7/MasR and natriuretic peptide/particulate guanylyl cyclase receptor-A pathways play a key role in cardiorenal disease protection. Even though individual activation of these pathways possesses cardiorenal protective effects. However, the dual activation of these pathways under stress conditions and the underlying mechanism has not been explored. The study aimed to investigate whether activation of these pathways by dual-acting peptide (DAP) shows a protective effect in-vitro in oxidative stress-induced renal epithelial cells. Oxidative stress was induced in renal epithelial NRK-52E cells with H₂O₂. Co-treatment with Ang 1-7, BNP, and DAP was given for 30 min. AT1, MasR, and pGCA expression were measured by RT-PCR. The markers of oxidative stress and apoptosis were measured by confocal microscopy and FACS analysis. A significant increase in AT1, renin, α-SMA, and NFk-β expression and a significant decrease in MasR and pGCA expression was observed in H₂O₂-induced cells. DAP improved H₂O₂-induced pathological changes in NRK-52E cells. The effect of DAP was superior to that of Ang1-7 and BNP alone. Interestingly, MasR and pGCA inhibitors could block the effect of DAP in H₂O₂-induced cells. DAP shows superior anti-RAAS activity, and it is effective against H₂O₂-induced oxidative stress, apoptosis, fibrosis, and inflammation compared to Ang1-7 and BNP alone. The protective effect is mediated by the dual activation of MasR and pGCA.