In mice lacking the GC-A receptor, 4 weeks of aldosterone and high salt caused accelerated hypertension, massive proteinuria, and severe podocyte injury compared to wild-type mice.
Does the endogenous natriuretic peptide/GC-A system protect against aldosterone-induced glomerular injury and oxidative stress in podocytes?
The endogenous natriuretic peptide/GC-A system protects against aldosterone-induced glomerular injury by locally inhibiting the renin-angiotensin-aldosterone system and oxidative stress in podocytes.
Natriuretic peptides produced by the heart in response to cardiac overload exert cardioprotective and renoprotective effects by eliciting natriuresis, reducing BP, and inhibiting cell proliferation and fibrosis. These peptides also antagonize the renin-angiotensin-aldosterone system, but whether this mechanism contributes to their renoprotective effect is unknown. Here, we examined the kidneys of mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides under conditions of high aldosterone and high dietary salt. After 4 weeks of administering aldosterone and a high-salt diet, GC-A knockout mice, but not wild-type mice, exhibited accelerated hypertension with massive proteinuria. Aldosterone-infused GC-A knockout mice had marked mesangial expansion, segmental sclerosis, severe podocyte injury, and increased oxidative stress. Reducing the BP with hydralazine failed to lessen such changes; in contrast, blockade of the renin-angiotensin-aldosterone system markedly reduced albuminuria, ameliorated podocyte injury, and reduced oxidative stress. Furthermore, treatment with the antioxidant tempol significantly reduced albuminuria and abrogated the histologic changes. In cultured podocytes, natriuretic peptides inhibited aldosterone-induced mitogen-activated protein kinase phosphorylation. Taken together, these results suggest that renoprotective properties of the endogenous natriuretic peptide/GC-A system may result from the local inhibition of the renin-angiotensin-aldosterone system and oxidative stress in podocytes.
Ogawa et al. (Fri,) conducted a other in Aldosterone-Induced Glomerular Injury. Aldosterone and high-salt diet in GC-A knockout mice vs. Wild-type mice was evaluated on Hypertension, proteinuria, and glomerular injury. In mice lacking the GC-A receptor, 4 weeks of aldosterone and high salt caused accelerated hypertension, massive proteinuria, and severe podocyte injury compared to wild-type mice.