Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition.
Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition.
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DOI：
10.1038/srep46624
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发表时间：
2017-04-21
影响因子：
4.6
通讯作者：
Yokoi H
中科院分区：
文献类型：
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作者：
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
鸟苷酰环酶-A(GC-A)信号转导通路是一种利钠肽受体，通过刺激尿钠和降低血压发挥肾脏保护作用。此前，我们在单肾切除、注射醛固酮和高盐喂养(ALDO)的全身性GC-A KO小鼠中发现，足细胞中p38丝裂原活化蛋白激酶(MAPK)的磷酸化增强，导致大量蛋白尿并高血压。在本研究中，我们研究了p38MAPK和GC-A信号之间的相互作用。给予p38 MAPK抑制剂FR167653、降低收缩压(SBP)、尿白蛋白排泄、节段性硬化症、足细胞损伤和细胞凋亡。为了进一步研究钠尿肽和p38MAPK在足细胞中的局部作用，我们产生了足细胞特异性(POD)GC-A条件性KO(CKO)小鼠。Aldo pod GC-A CKO小鼠表现为尿白蛋白排泄增加，系膜明显扩张，足细胞损伤和细胞凋亡，但未见血压升高。FR167653在不降低SBP的情况下也能抑制尿白蛋白排泄。最后，我们发现心钠素增加了MAPK磷酸酶-1(MKP-1)的磷酸化，同时抑制了p38MAPK的磷酸化，从而导致了凋亡相关基因Bax的mRNA表达和Bax/Bcl2比值的降低。这些结果表明，利钠肽通过抑制足细胞p38MAPK的磷酸化而发挥肾脏保护作用。
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.