Abstract
Despite optimal control of hyperglycaemia, hypertension, and dyslipidaemia, the number of patients with diabetic nephropathy (DN) continues to grow. Strategies to target various signaling pathways to prevent DN have been intensively investigated in animal models and many have been proved to be promising. However, targeting these pathways once kidney disease is established, remain unsatisfactory. The clinical scenario is that patients with diabetes mellitus often present with established kidney damage and need effective treatments to repair and reverse the kidney damage. In this studies, eNOS-/- mice were administered with streptozotocin to induce diabetes. At 24 weeks, at which time we have previously demonstrated albuminuria and pathological changes of diabetic nephropathy, mice were randomised to receive TRAM34 subcutaneously, a highly selective inhibitor of potassium channel KCa3.1 or DMSO (vehicle) for a further 14 weeks. Albuminuria was assessed, inflammatory markers (CD68, F4/80) and extracellular matrix deposition (type I collagen and fibronectin) in the kidneys were examined. The results clearly demonstrate that TRAM34 reduced albuminuria, decreased inflammatory markers and reversed extracellular matrix deposition in kidneys via inhibition of the TGF-β1 signaling pathway. These results indicate that KCa3.1 blockade effectively reverses established diabetic nephropathy in this rodent model and provides a basis for progressing to human studies.
Highlights
Diabetic nephropathy is the leading cause of end-stage renal failure, accounting for 35–40% of all new cases requiring dialysis therapy throughout the world
We have previously shown that blockade of KCa3.1 prevented the development of extracellular matrix deposition and fibrosis in diabetic nephropathy through inhibition of the transforming growth factor β-1 (TGF-β1)/Smad signaling pathway [11], limiting activation of renal fibroblasts [20], suppression of TGF-β1 induced monocyte chemoattractant protein-1 (MCP-1) expression and high glucose induced chemokine (C-C motif) ligand 20 (CCL20) expression in renal proximal tubular cells [21, 22]
KCa3.1 blocker TRAM34 ameliorated the renal injury in mice with established diabetic nephropathy
Summary
Diabetic nephropathy is the leading cause of end-stage renal failure, accounting for 35–40% of all new cases requiring dialysis therapy throughout the world. The increasing incidence of diabetes elevates diabetic nephropathy to one of the most
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