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Sci Rep. 2017 Apr 21;7:46624. doi: 10.1038/srep46624.

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

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Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Department of Nephrology and Kidney Research, Shizuoka General Hospital, Shizuoka, Japan.
Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Japan.
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan.
Department of Endocrinology and Diabetes, Toyooka Public Hospital, Toyooka, Japan.
Children's Renal Unit, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK.
Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Japan.
Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.


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.

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