Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, and University of Sydney, St Leonards, Sydney, New South Wales, Australia.
Diabetes. 2013 Aug;62(8):2923-34. doi: 10.2337/db13-0135. Epub 2013 May 8.
The Ca(2+)-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.
钙激活钾通道 KCa3.1 介导与血管功能障碍相关的细胞信号转导过程。然而，KCa3.1 在糖尿病肾病中的作用尚不清楚。我们试图评估 KCa3.1 是否介导两种糖尿病肾病动物模型中肾脏纤维化的发展。野生型和 KCa3.1(-/-) 小鼠，其次是 eNOS(-/-) 小鼠，通过链脲佐菌素诱导糖尿病，然后用/不用 KCa3.1 的选择性抑制剂（TRAM34）治疗。我们的结果表明，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 TRAM34 治疗的糖尿病 eNOS(-/-) 小鼠的白蛋白与肌酐比值也显著降低。与糖尿病野生型小鼠相比，糖尿病 KCa3.1(-/-) 小鼠肾脏中单核细胞趋化蛋白 1（MCP-1）、细胞间黏附分子 1（ICAM1）、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）。同样，TRAM34 降低了上述在糖尿病 eNOS(-/-) 小鼠中描述的炎症和纤维化标志物的表达。此外，在两种动物模型中阻断 KCa3.1 通道导致转化生长因子-β1（TGF-β1）和 TGF-β1 型 II 受体（TβRII）以及 Smad2/3 磷酸化减少。我们的结果提供了证据表明，KCa3.1 通过 TGF-β1/Smad 信号通路介导糖尿病肾病中的肾脏纤维化。阻断 KCa3.1 可能是糖尿病肾病患者治疗干预的新靶点。
