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2017 ; 7
(ä): 46624
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Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular
injury evoked by aldosterone through p38 mitogen-activated protein kinase
inhibition
#MMPMID28429785
Kato Y
; Mori K
; Kasahara M
; Osaki K
; Ishii A
; Mori KP
; Toda N
; Ohno S
; Kuwabara T
; Tokudome T
; Kishimoto I
; Saleem MA
; Matsusaka T
; Nakao K
; Mukoyama M
; Yanagita M
; Yokoi H
Sci Rep
2017[Apr]; 7
(ä): 46624
PMID28429785
show ga
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.