Abstract
Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.
Highlights
Reactivation of renin-angiotensin-aldosterone system through positive feedback[3], and the induction of reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs) in the kidney[4]
We investigated whether atrial natriuretic peptide (ANP) can inhibit expression of apoptosis-related proteins induced by activation of p38 MAPK in cultured human podocytes
The present study demonstrated that blockade of p38 MAPK ameliorates glomerular injury in ALDO systemic guanylyl cyclase-A (GC-A) KO mice
Summary
Reactivation of renin-angiotensin-aldosterone system through positive feedback[3], and the induction of reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs) in the kidney[4]. The site of action of aldosterone remains obscure, as aldosterone has been reported to exert its effect on podocytes[5], mesangial cells[6], endothelial cells[7], and tubular cells[8]. We previously demonstrated massive albuminuria, mesangial expansion, segmental sclerosis, and podocyte-injury with the elevation of systolic blood pressure in uninephrectomized, aldosterone-infused, and high salt diet-fed (ALDO) systemic GC-A knockout (KO) mice[10]. In the previous model, reduced blood pressure with the use of hydralazine fails to ameliorate renal injury; blockade of the renin angiotensin system by an angiotensin receptor blocker (ARB) or antioxidant tempol reduces glomerular injury[10]. Our previous report may indicate that natriuretic peptides protect podocytes from aldosterone-induced renal injury, the precise site of action of natriuretic peptides/GC-A system, and the mechanism underlying amelioration of aldosterone-induced glomerular injury by natriuretic peptides have yet to be elucidated. We generated podocyte-specific (pod) GC-A conditional KO (cKO) mice and examined the effects of p38 MAPK in systemic and pod GC-A cKO mice administered aldosterone, uninephrectomy, and a high salt diet
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