Natriuretic Peptide Receptor Guanylyl Cyclase-A Protects Podocytes from Aldosterone-Induced Glomerular Injury

Abstract

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.

MicroRNA-26a inhibits TGF-β-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy

“…Western blotting Western blotting was performed as previously described [30] (for further details, please refer to the ESM Methods).…”

Oxidative Stress in Hypertension: Role of the Kidney

“…Aldosterone also has been implicated in ROS-dependent podocyte injury and MC proliferation (20) and also may be involved in a feed-forward signaling between ROS and the RAAS (20, 139,202,212). Tempol preserved podocyte function and attenuated glomerulosclerosis in rats with aldosterone plus salt-induced hypertension (202).…”

“…Tempol preserved podocyte function and attenuated glomerulosclerosis in rats with aldosterone plus salt-induced hypertension (202). Mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides and given aldosterone and a high-salt diet increased oxidative stress, podocyte injury, and albuminuria, which were ameliorated by tempol or an ARB (212). The authors attributed the renoprotective properties of the GC-A system to a local inhibition of the RAAS and oxidative stress in podocytes, independent of BP.…”

Clinical efficacy of dual inhibitor of neprilisin and AT1‑angiotensin receptors LCZ696 (sakubitril/valsartan) in chronic heart failure patients with impaired renal function

“…У трансген-ных мышей с делецией гена ГЦ-А рецептора, напро-тив, резко усиливаются вызываемые АТ II процессы атрофии клеток проксимальных канальцев, их эпите-лиально-мезенхимальной трансформации и склероти-ческого повреждения околоканальцевого интерстиция, лежащие в основе тубулоинтерстициального фиброза почечной ткани [3]. У таких животных значительно усиливается также негативное действие альдостерона в почечных клубочках, которое проявляется в более выраженном повреждении подоцитов, увеличении объема мезангиального матрикса, гломерулосклерозе и обильной протеинурии [31].…”