Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function

Abstract

The cardiac natriuretic peptides (NPs), atrial NP and B-type NP, regulate fluid homeostasis and arterial BP through renal actions involving increased GFR and vascular and tubular effects. Guanylyl cyclase-A (GC-A), the transmembrane cGMP-producing receptor shared by these peptides, is expressed in different renal cell types, including podocytes, where its function is unclear. To study the effects of NPs on podocytes, we generated mice with a podocyte-specific knockout of GC-A (Podo-GC-A KO). Despite the marked reduction of GC-A mRNA in GC-A KO podocytes to 1% of the control level, Podo-GC-A KO mice and control littermates did not differ in BP, GFR, or natriuresis under baseline conditions. Moreover, infusion of synthetic NPs similarly increased the GFR and renal perfusion in both genotypes. Administration of the mineralocorticoid deoxycorticosterone-acetate (DOCA) in combination with high salt intake induced arterial hypertension of similar magnitude in Podo-GC-A KO mice and controls. However, only Podo-GC-A KO mice developed massive albuminuria (controls: 35-fold; KO: 5400-fold versus baseline), hypoalbuminemia, reduced GFR, and marked glomerular damage. Furthermore, DOCA treatment led to decreased expression of the slit diaphragm-associated proteins podocin, nephrin, and synaptopodin and to enhanced transient receptor potential canonical 6 (TRPC6) channel expression and ATP-induced calcium influx in podocytes of Podo-GC-A KO mice. Concomitant treatment of Podo-GC-A KO mice with the TRPC channel blocker SKF96365 markedly ameliorated albuminuria and glomerular damage in response to DOCA. In conclusion, the physiologic effects of NPs on GFR and natriuresis do not involve podocytes. However, NP/GC-A/cGMP signaling protects podocyte integrity under pathologic conditions, most likely by suppression of TRPC channels.

Sustained Activation of Guanylate Cyclase-A with TDT, a Natriuretic Peptide Derivative, Exhibits Cardiorenal Protection in Dahl Salt-Sensitive Hypertensive Rats

“…In this context, it is important that TDT treatment reduced TRPC activity both in vitro and in vivo, contributing to the prevention of glomerulosclerosis. Interestingly, we also demonstrated that TRPC-mediated calcium influx was inhibited by PKG inhibitor, consistent with the previous report that the renal dysfunction by GC-A gene ablation is attenuated by a TRPC inhibitor (Staffel et al, 2017).…”

“…Further studies would be required to make clear whether TDT shows clinical benefits additive to NEP inhibitors. Recent studies using genetically modified mice showed that podocyte-specific ablation of the NP receptor GC-A gene results in increased susceptibility to renal injury (Staffel et al, 2017), indicating that GC-A in podocytes play important roles in renal protection; however, it remains to be fully elucidated whether pharmacological activation of the NP receptor protects kidneys from chronic stress, because conventional NPs are rapidly degraded by NEP. Here, using TDT, we successfully demonstrated that chronic activation of GC-A by long-acting NPs prevented renal dysfunction accompanied by protection of podocytes.…”

Crrl269

“…Lines of evidence support that the pGC-A/cGMP signaling pathway plays a critical role maintaining renal physiological integrity and protecting the kidney from injury [40][41][42][43][44] . One of the key pathophysiological pathways targeted by pGC-A is apoptosis.…”

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

“…ПНП, сериновая протеаза, превращающая проПНП в активный пептид, НЭП и ГЦА-рецепторы экспрессированы в клетках нефрона, особенно в проксимальных канальцах и собирательных трубках, локализованных в мозговом веществе почек. Высокая плотность ГЦА-рецепторов обнаружена в подоцитах клубочков и гломерулярных мезангиаль-ных клетках [25][26][27]. Циркулирующие НУП и образу-ющийся локально ПНП прямо ингибируют реабсорб-цию натрия в проксимальном и дистальном сегментах нефрона, ослабляя стимулирующий эффект НА и АТ II [28], и способствуют увеличению СКФ, вызывая дилатацию прегломерулярных и сужение постгломе-рулярных артериол клубочков [29].…”