735 Role of P38 MAPK in aldosterone-induced glomerular injury in natriuretic peptide receptor-A deficient mice

Abstract

Background: Aldosterone plays an important role in pathophysiology of renal injury. We already reported that natriuretic peptide receptor guanylyl cyclase-A (GC-A) signaling, with potential anti-aldosterone actions, exerts renoprotective effects in various mouse nephropathies including subtotal nephrectomy, immune-mediated renal injury and diabetic nephropathy. Furthermore, we demonstrated that GC-A knockout (KO) mice with aldosterone and sodium overload exhibited accelerated hypertension with massive proteinuria (∼300-fold urinary albumin excretion from baseline). Aldosterone infusion also increased phosphorylation of ERK and p38 MAP kinase (MAPK) mainly in podocytes of GC-A KO mice, but their role remains elusive. Methods: To explore the role of p38 MAPK in this model, we investigated effects of p38 MAPK inhibition. Two weeks after uninephrectomy, mice were administered with aldosterone (0.2 μg/kg/min) subcutaneously using an osmotic minipump with 6% sodium diet, and with or without hydralazine or a p38 MAPK inhibitor (FR167653, 33 mg/kg/day) in drinking water. We examined BP, albumin excretion, and histological findings. Results: Aldosterone administration increased systolic BP by ∼50 mmHg in GC-A KO mice compared with wild-type mice, and FR treatment modestly but significantly decreased BP. Although hydralazine treatment normalized BP in GC-A KO, urinary albumin excretion did not change. Interestingly, urinary albumin excretion was dramatically decreased by 90% in aldosterone-infused GC-A KO with FR treatment. Glomerular hypertrophy, mesangial expansion, and podocyte injury were markedly ameliorated in these mice with FR treatment. Conclusions: These results suggest that p38 MAPK plays a crucial role connecting aldosterone and GC-A pathways, and could be a potential target against aldosterone-induced glomerular injury.