Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy.
Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy.
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DOI：
10.1007/s00125-015-3796-0
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发表时间：
2016-02
期刊：
影响因子：
8.2
通讯作者：
Jandeleit-Dahm KA
中科院分区：
文献类型：
--
作者：
Jha JC;Thallas-Bonke V;Banal C;Gray SP;Chow BS;Ramm G;Quaggin SE;Cooper ME;Schmidt HH;Jandeleit-Dahm KA
足细胞形态和功能的改变与蛋白尿和糖尿病肾病的进展有关。NADPH氧化酶4 （NOX4）是肾脏活性氧（ROS）的主要来源，在高葡萄糖的反应中，NOX4在足细胞中上调。我们在糖尿病肾病模型中使用足细胞特异性nox4缺陷小鼠评估了nox4衍生ROS在足细胞中的作用，主要关注蛋白尿和超肾小球结构损伤的发展。在雄性floxedNox4和足细胞特异性敲除（podNox4KO）小鼠中研究了链脲佐菌素诱导的糖尿病相关肾脏结构和功能的变化。我们评估了蛋白尿、肾小球细胞外基质积累和肾小球硬化、ROS和炎症标志物，以及肾小球基底膜厚度、足细胞的消失和足细胞特异性蛋白nephrin的表达。链脲佐菌素诱导的糖尿病小鼠足细胞特异性Nox4缺失与血管内皮生长因子（VEGF）表达降低和预防糖尿病诱导的肾素表达降低相关，从而减轻蛋白尿。此外，足细胞特异性Nox4缺失减少了肾小球IV型胶原和纤维连接蛋白的积累，肾小球硬化和系膜扩张，以及肾小球基底膜厚度。此外，足细胞特异性nox4缺陷小鼠中，糖尿病诱导的肾脏ROS、肾小球单核细胞化学引诱蛋白-1 （MCP-1）和蛋白激酶C α (PKC-α)的升高被减弱。总的来说，本研究表明，在实验性糖尿病中，Nox4的表达通过促进足细胞病变、蛋白尿和细胞外基质积累而产生有害作用，强调了Nox4作为新型肾保护药物靶点的作用。
Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice. Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents.
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