G protein-coupled estrogen receptor activation attenuates cisplatin-induced CKD in C57BL/6 mice: An insight into sex-related differences

Abstract

Gender contributes to differences in incidence and progression of chronic kidney disease (CKD) post-cisplatin therapy. This study aims at investigating the potential effect of G1 compound, a GPER agonist, on attenuating cisplatin-induced CKD. To induce CKD in male, intact female, and ovariectomized (OVX) mice, CKD was induced by injecting two cycles of 2.5 mg/kg cisplatin with a 16-day recovery period between cycles). G1 (50 or 100 μg/kg was administered daily for 6 weeks. Severity of renal damage was more pronounced in males than females. Interestingly, OVX resulted in renal damage that is non-significant compared to males and significantly higher than females. G1 improved renal function and blood flow as evidenced by reduction of serum creatinine and elevation of creatinine clearance, NO production, and reduction of ET1. This renoprotective effect could be attributed to its immunomodulatory effect regulated by TGF-β that shifted the balance to favor anti-inflammatory cytokine production (increased IL-10) rather than pro-inflammatory cytokines (decreased Th17 expression). Reduction of TGF-β activation also inhibited epithelial-to-mesenchymal transition that eventually ameliorated CKD development. Antioxidant potential of G1 has been demonstrated by upregulation of Nrf2 and subsequent antioxidant enzymes. These data suggest that G1 could be a promising therapeutic tool to attenuate CP-induced CKD.