Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition

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.

Aldosterone Induces DNA Damage and Activation of Nrf2 Mainly in Tubuli of Mouse Kidneys

“…This damage was strictly dose dependent, but already the lowest dose resulted in a substantial increase in four out of five kidney function related parameters, suggesting that lower doses also would have the potential to damage the tissue. Comparable results, increased albumin excretion induced by aldosterone without elevated blood pressure, were published also by other groups [ 26 , 27 ].…”

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

“…In addition, we demonstrated that TDT protected not only podocytes but also tubules, even at a low dose. Consistently, Kato et al (2017) reported that systemic GC-A KO mice are more susceptible to renal damage than podocyte-specific GC-A KO mice in a blood pressure-independent manner, which indicates the importance of other renal cells, including tubules, in the signaling of NPs. Further investigations regarding the direct protection of tubules by GC-A activation will be required.…”

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases

“…The expression percentage was significantly higher in immune-mediated disease, including membranous nephropathy (46.7%), IgA nephropathy (66.7%), lupus nephritis (87.5%), and acute proliferative glomerulonephritis (100%), than in normal kidney samples (16.7%) ( P < 0.05), whereas there was no significant difference between minimal-change disease and normal kidney. The relation between FcRn and p38MAPK signaling may be of pathogenetic significance since p38MAPK appears to be a major profibrotic pathway in diabetic ( 55 ), experimental nephrotic syndrome ( 56 ), and hypertensive kidney disease ( 57 ), whose inhibition leads to reduced blood pressure, sclerosis, podocyte injury, and apoptosis ( 58 ). In particular, one may postulate that activation of the β 2 M containing FcRn (e.g., by proteinuria) may trigger pathways of fibrosis inside the kidney through the p38MAPK pathway.…”