Wnt/β-catenin signalling pathway mediates high glucose induced cell injury through activation of TRPC6 in podocytes

Z Li, J Xu, P Xu, S Liu, Z Yang
Cell Proliferation 2013, 46 (1): 76-85

OBJECTIVES: Diabetic nephropathy is a major complication of diabetes and a frequent cause of end-stage renal disease and recent studies suggest that podocyte damage may play a role in the pathogenesis of this. At early onset of diabetic nephropathy there is podocyte drop-out, which is thought to provoke glomerular albuminuria and subsequent glomerular injury; however, the underlying molecular mechanisms of this remain poorly understood. Here we report that we tested the hypothesis that early diabetic podocyte injury is caused, at least in part, by up-regulation of transient receptor potential cation channel 6 (TRPC6), which is regulated by the canonical Wnt signalling pathway, in mouse podocytes.

MATERIALS AND METHODS: Mechanism of injury initiation in mouse podocytes, by high concentration of D-glucose (HG, 30 mM), was investigated by MTT, flow cytometry, real-time quantitative PCR, and western blot analysis.

RESULTS: HG induced apoptosis and reduced viability of differentiated podocytes. It caused time-dependent up-regulation of TRPC6 and activation of the canonical Wnt signalling pathway, in mouse podocytes. In these cells, blockade of the Wnt signalling pathway by dickkopf related protein 1 (Dkk1) resulted in effective reduction of TRPC6 up-regulation and amelioration of podocyte apoptosis. Furthermore, reduction of cell viability induced by HG was attenuated by treatment with Dkk1.

CONCLUSION: These findings indicate that the Wnt/β-catenin signalling pathway may potentially be active in pathogenesis of TRPC6-mediated diabetic podocyte injury.

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