Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy
Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy
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DOI：
10.2337/db18-0837
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发表时间：
2019-05-01
期刊：
影响因子：
7.7
通讯作者：
Geraldes, Pedro
中科院分区：
文献类型：
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作者：
Denhez, Benoit;Rousseau, Marina;Geraldes, Pedro
糖尿病肾病(DN)仍然是终末期肾病的主要原因。高血糖诱导的足细胞功能障碍是糖尿病肾病患者肾功能损害的主要原因。以往的研究表明，糖尿病时丝裂原活化蛋白激酶(MAPK)的激活促进足细胞功能障碍和细胞死亡。双特异性磷酸酶(DUSPs)是一类主要负责MAPK抑制的磷酸酶家族。在这项研究中，我们证明了糖尿病和高糖暴露降低了培养的足细胞和肾小球中DUSP4的表达。糖尿病诱导的DUSP4减少增加了p38和c-jun氨基末端激酶(JNK)的活性和足细胞功能障碍。DUSP4过表达可抑制高糖诱导的p38、JNK、caspase3/7活性和NADPH氧化酶4的表达。DUSP4基因缺失加剧了糖尿病小鼠的蛋白尿，增加了系膜扩张和肾小球纤维化。这些形态变化与足突深度消失、细胞死亡和持续的p38和JNK激活有关。此外，抑制蛋白激酶C-Delta可阻止糖尿病小鼠足细胞和肾皮质中DUSP4的表达下降和p38/JNK的激活。对糖尿病患者肾皮质DUSP4表达的分析表明，DUSP4mRNA表达降低与估计肾小球滤过率(
Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease. Hyperglycemia-induced podocyte dysfunction is a major contributor of renal function impairment in DN. Previous studies showed that activation of mitogen-activated protein kinase (MAPK) in diabetes promotes podocyte dysfunction and cell death. Dual specificity phosphatases (DUSPs) are a family of phosphatases mainly responsible for MAPK inhibition. In this study, we demonstrated that diabetes and high glucose exposure decreased DUSP4 expression in cultured podocytes and glomeruli. Diabetes-induced DUSP4 reduction enhanced p38 and c-Jun N-terminal kinase (JNK) activity and podocyte dysfunction. The overexpression of DUSP4 prevented the activation of p38, JNK, caspase 3/7 activity, and NADPH oxidase 4 expression induced by high glucose level exposure. Deletion of DUSP4 exacerbated albuminuria and increased mesangial expansion and glomerular fibrosis in diabetic mice. These morphological changes were associated with profound podocyte foot process effacement, cell death, and sustained p38 and JNK activation. Moreover, inhibition of protein kinase C-delta prevented DUSP4 expression decline and p38/JNK activation in the podocytes and renal cortex of diabetic mice. Analysis of DUSP4 expression in the renal cortex of patients with diabetes revealed that decreased DUSP4 mRNA expression correlated with reduced estimated glomerular filtration rate (