Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure.
Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure.
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DOI：
10.1038/srep27192
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发表时间：
2016-06-07
影响因子：
4.6
通讯作者：
Mukoyama M
中科院分区：
文献类型：
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作者：
Ohno S;Yokoi H;Mori K;Kasahara M;Kuwahara K;Fujikura J;Naito M;Kuwabara T;Imamaki H;Ishii A;Saleem MA;Numata T;Mori Y;Nakao K;Yanagita M;Mukoyama M
N型和L型钙通道的药物阻断可减轻肾病患者的肾损伤。N型钙通道α1亚单位Cav2.2的特异性阻断在糖尿病肾病中的意义尚不清楚。为了检查功能作用，我们在C57 BLKS背景下将Cav2.2−/−小鼠与db/db（糖尿病）小鼠交配。Cav2.2定位于肾小球，包括足细胞和远端肾小管细胞。与糖尿病Cav2.2+/+小鼠相比，糖尿病Cav2.2 −/−小鼠显著减少了尿白蛋白排泄、肾小球超滤、血糖水平、组织学恶化和收缩压（SBP），尿儿茶酚胺减少。有趣的是，糖尿病杂合Cav2.2+/−小鼠也减少了白蛋白尿，尽管它们表现出与糖尿病Cav2.2+/+小鼠相当的收缩压、交感神经活性和肌酐清除率。与此同时，与尼群地平糖尿病小鼠相比，西尼地平，一种N-/L-型钙通道阻滞剂，显示出减少蛋白尿和改善肾小球变化。在培养的足细胞中，去极化依赖性钙反应被Cav2.2特异性抑制剂ω-芋螺毒素降低。此外，ω-芋螺毒素、西尼地平或丝裂原活化蛋白激酶激酶抑制剂可消除足细胞中转化生长因子-β（TGF-β）对nephrin的减少。总之，Cav2.2抑制对糖尿病肾病的进展发挥肾保护作用，部分通过保护足细胞。
Pharmacological blockade of the N- and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Cav2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Cav2.2−/− mice with db/db (diabetic) mice on the C57BLKS background. Cav2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Cav2.2−/− mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Cav2.2+/+ mice. Interestingly, diabetic heterozygous Cav2.2+/− mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Cav2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Cav2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Cav2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.