title: Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice.
abstract: 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.
authors: Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, and University of Sydney, St Leonards, Sydney, New South Wales, Australia.
authors: Chunling
authors: C
authors: Huang
authors: Sylvie
authors: S
authors: Shen
authors: Qing
authors: Q
authors: Ma
authors: Jason
authors: J
authors: Chen
authors: Anthony
authors: A
authors: Gill
authors: Carol A
authors: CA
authors: Pollock
authors: Xin-Ming
authors: XM
authors: Chen
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D024141:Collagen Type IV; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C411671:TRAM 34; D053773:Transforming Growth Factor beta1
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