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Aldosterone is a key molecule in glomerular injury and tubulointerstitial fibrosis. Natriuretic peptide receptor/guanylyl cyclase-A (GC-A) signaling exerts renoprotective effects by eliciting natriuresis, reducing blood pressure, and inhibiting fibrosis. We demonstrated that uninephrectomized GC-A knockout (KO) mice with aldosterone and sodium overload exhibited accelerated hypertension with massive proteinuria. In this model, inhibition of p38 MAP kinase (MAPK) ameliorated renal injury. However, local effect of natriuretic peptide receptor/GC-A signaling in podocyte is not fully elucidated.To explore the role of GC-A signaling in podocyte, we generated podocytes-specific GC-A KO mice (pod-GC-A cKO). Pod-GC-A cKO mice or wild-type mice were uninephrectomized and then treated with high salt orally and aldosterone subcutaneously using an osmotic minipump for 4 weeks.Although systolic blood pressure was not different between control and pod-GC-A cKO mice, pod-GC-A cKO mice showed significantly increased urinary albumin excretion by 13-fold (n = 7, p < 0.01). Glomerular hypertrophy, mesangial expansion and apoptosis determined by TUNEL assay were increased in pod-GC-A cKO mice. Urinary potassium excretion was not affected between two groups. Administration of aldosterone increased phosphorylation of p38 MAPK mainly in podocytes. In vitro study, overexpression of MKK3 in cultured human podocytes upregulated the phosphorylation of p38 MAPK and BAX mRNA expression. Such induction was significantly inhibited by the administration of ANP.These results suggest that endogenous natriuretic peptide/GC-A system on podocytes acts renoprotective and anti-apoptotic roles in aldosterone-induced renal injury by inhibiting phosphorylation of p38 MAPK.