The Noncanonical Wnt5a-Ca Pathway Mediates Mitochondrial Dysfunction in the Progression of Diabetic Nephropathy via the Mitochondrial Calcium Uniporter.

Abnormal Wnt5a expression, mitochondrial abnormalities and calcium overload have been detected in many metabolic diseases. However, the association of Wnt5a-Ca and mitochondrial dysfunction in diabetic nephropathy (DN) progression remains unknown. We used streptozotocin-induced DBA2/J male mice as a DN model. The mice were treated with losartan (10 mg/kg/d12 w) or losartan (10 mg/kg/d12 w) + levamlodipine (5 mg/kg/d*12 w). High glucose (HG) (40 mmol/L)-induced HK-2 cells were used for in vitro experiments. Wnt5a and mitochondrial calcium uniporter (MCU) expression, mitochondrial dynamics, morphological changes and Ca concentration were detected in different groups. Levamlodipine, a kind of calcium channel blocker, in combination with losartan ameliorated tubular injury and reversed mitochondrial fragmentation and dynamic dysfunction more efficiently than losartan alone in diabetic mice. Wnt5a induced Ca uptake and aggravated mitochondrial fusion-fission disorder in HG-stimulated HK-2 cells. In addition, increased MCU formation was found in the mitochondria of tubular cells under HG stimulation and was upregulated by the activation of the Wnt5a-Ca pathway. Our study showed that the Wnt5a-Ca signalling pathway was involved in Ca overload-induced mitochondrial dysfunction possibly through MCU in tubular injury and DN progression. A calcium channel blocker in combination with a renin-angiotensin system inhibitor (RASi) could be a promising therapeutic strategy in DN patients.