Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome
Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome
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DOI：
10.1681/asn.2004121084
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发表时间：
2005-09-01
影响因子：
13.6
通讯作者：
Nakao, K
中科院分区：
文献类型：
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作者：
Koshikawa, M;Mukoyama, M;Nakao, K
足细胞在维持正常肾小球功能和结构方面起着重要作用，足细胞损伤可导致蛋白尿和肾小球硬化。丝裂原活化蛋白激酶家族（MAPK；胞外信号调节激酶[ERK]， c-Jun n-末端激酶和p38）可能与各种肾小球疾病的进展有关，但MAPK在足细胞损伤中的作用尚不清楚。本研究检测了p38 MAPK磷酸化在临床肾小球病伴足细胞损伤，以及大鼠嘌呤霉素氨基核苷（PAN）肾病和小鼠阿霉素（ADR）肾病中的作用。用p38 MAPK抑制剂FR167653治疗的效果也在啮齿动物模型中进行了研究。在人足细胞损伤疾病中，在足细胞中观察到p38 MAPK磷酸化升高。在PAN和ADR肾病中，p38 MAPK和ERK的磷酸化是明显的，但是短暂的，在明显的蛋白尿之前。用FR167653对PAN或ADR肾病进行预处理（第2天至第14天，皮下），完全抑制p38 MAPK的激活，减弱ERK磷酸化，完全抑制蛋白尿。电镜和免疫组化检测结果显示，FR167653能显著改善足细胞损伤。此外，FR167653早期治疗可有效预防ADR肾病慢性期肾小球硬化和肾功能障碍。在培养的足细胞中，PAN或氧化应激诱导p38 MAPK磷酸化和肌动蛋白重组，FR167653抑制这种变化。这些发现表明，MAPK的激活对于足细胞损伤是必要的，这表明p38 MAPK，可能还有ERK，应该成为蛋白尿肾小球疾病治疗干预的潜在靶点。
Podocytes play an important role in maintaining normal glomerular function and structure, and podocyte injury leads to proteinuria and glomerulosclerosis. The family of mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase, and p38) may be implicated in the progression of various glomerulopathies, but the role of MAPK in podocyte injury remains elusive. This study examined phosphorylation of p38 MAPK in clinical glomerulopathies with podocyte injury, as well as in rat puromycin aminonucleoside (PAN) nephropathy and mouse adriamycin (ADR) nephropathy. The effect of treatment with FR167653, an inhibitor of p38 MAPK, was also investigated in rodent models. In human podocyte injury diseases, the increased phosphorylation of p38 MAPK was observed at podocytes. In PAN and ADR nephropathy, the phosphorylation of p38 MAPK and ERK was marked but transient, preceding overt proteinuria. Pretreatment with FR167653 (day -2 to day 14, subcutaneously) to PAN or ADR nephropathy completely inhibited p38 MAPK activation and attenuated ERK phosphorylation, with complete suppression of proteinuria. Electron microscopy and immunohistochemistry for nephrin and connexin43 revealed that podocyte injury was markedly ameliorated by FR167653. Furthermore, early treatment with FR167653 effectively prevented glomerulosclerosis and renal dysfunction in the chronic phase of ADR nephropathy. In cultured podocytes, PAN or oxidative stress induced the phosphorylation of p38 MAPK along with actin reorganization, and FR167653 inhibited such changes. These findings indicate that the activation of MAPK is necessary for podocyte injury, suggesting that p38 MAPK and, possibly, ERK should become a potential target for therapeutic intervention in proteinuric glomerulopathies.