Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice.
Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice.
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作者：
Huang C;Shen S;Ma Q;Chen J;Gill A;Pollock CA;Chen XM
Ca ~（2+）激活的K ~+通道KCa ~（3.1）介导与血管功能障碍相关的细胞信号传导过程。然而，KCa 3.1在糖尿病肾病中的作用尚不清楚。我们试图评估KCa 3.1是否介导了两种糖尿病肾病动物模型中肾纤维化的发展。野生型和KCa3.1−/−小鼠，其次是eNOS−/−小鼠，用链脲佐菌素诱导糖尿病，然后用/不用KCa3.1的选择性抑制剂（TRAM 34）治疗。我们的研究结果表明，与糖尿病野生型小鼠相比，糖尿病KCa3.1−/−小鼠的白蛋白与肌酐比值显著降低，与糖尿病小鼠相比，用TRAM 34治疗的糖尿病eNOS−/−小鼠的白蛋白与肌酐比值显著降低。与糖尿病野生型小鼠相比，糖尿病KCa 3.1 −/−小鼠肾脏中单核细胞趋化蛋白1（MCP-1）、细胞间粘附分子1（ICAM 1）、F4/80、纤溶酶原激活物抑制剂1（PAI-1）以及III型和IV型胶原的表达显著降低（P < 0.01）。类似地，TRAM 34减少了糖尿病eNOS−/−小鼠中上述炎症和纤维化标志物的表达。此外，在两种动物模型中阻断KCa 3.1通道导致转化生长因子-β1（TGF-β1）和TGF-β1 II型受体（TβRII）减少以及Smad 2/3磷酸化。我们的研究结果为KCa3.1通过TGF-β1/Smad信号通路介导糖尿病肾病的肾纤维化提供了证据。阻断KCa3.1可能是糖尿病肾病患者治疗干预的新靶点。
The Ca2+-activated K+ channel KCa3.1 mediates cellular signaling processes associated with dysfunction of vasculature. However, the role of KCa3.1 in diabetic nephropathy is unknown. We sought to assess whether KCa3.1 mediates the development of renal fibrosis in two animal models of diabetic nephropathy. Wild-type and KCa3.1−/− mice, and secondly eNOS−/− mice, had diabetes induced with streptozotocin and then were treated with/without a selective inhibitor of KCa3.1 (TRAM34). Our results show that the albumin-to-creatinine ratio significantly decreased in diabetic KCa3.1−/− mice compared with diabetic wild-type mice and in diabetic eNOS−/− mice treated with TRAM34 compared with diabetic mice. The expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM1), F4/80, plasminogen activator inhibitor type 1 (PAI-1), and type III and IV collagen significantly decreased (P < 0.01) in kidneys of diabetic KCa3.1−/− mice compared with diabetic wild-type mice. Similarly, TRAM34 reduced the expression of the inflammatory and fibrotic markers described above in diabetic eNOS−/− mice. Furthermore, blocking the KCa3.1 channel in both animal models led to a reduction of transforming growth factor-β1 (TGF-β1) and TGF-β1 type II receptor (TβRII) and phosphorylation of Smad2/3. Our results provide evidence that KCa3.1 mediates renal fibrosis in diabetic nephropathy through the TGF-β1/Smad signaling pathway. Blockade of KCa3.1 may be a novel target for therapeutic intervention in patients with diabetic nephropathy.
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