Bone morphogenetic protein 4-associated mitochondrial dysfunction in diabetic nephropathy involves Parkin downregulation

Background: Diabetic nephropathy (DN) is characterized by mesangial expansion and mitochondrial dysfunction. Although bone morphogenetic protein 4 (BMP4) is a pro-fibrotic factor in DN, its role in mesangial mitochondrial homeostasis remains unclear. This study investigated whether a decrease in Parkin is involved in mitochondria-related abnormalities following BMP4 stimulation. A mesangial cell line overexpressing Parkin was used to assess the role of Parkin under BMP4 stimulation. Mitochondrial function and the expression of Parkin and related genes were analyzed. Results: In STZ-induced diabetic mice, mesangial expansion was accompanied by mitochondrial abnormalities, increased BMP4 expression, diminished mtDNA copy number, and decreased expression of Parkin and related genes. In cultured mesangial cells, BMP4 stimulation was accompanied by a decrease in Parkin expression and reduced mitochondria-related indices, including decreased expression of mitochondrial function-related genes, reduced ATP production, and loss of membrane potential. The BMP4-induced changes in gene expression and mitochondrial functional indices were ameliorated by ALK inhibition. Furthermore, Parkin overexpression ameliorated BMP4-induced decreases in gene expression and mitochondrial functional indices. Conclusion: These findings suggest that decreased Parkin expression associated with BMP4 stimulation may be one of the molecular alterations contributing to mitochondria-related abnormalities in mesangial cells. Disrupted mitochondrial homeostasis accompanied by decreased Parkin expression may represent a candidate therapeutic pathway in DN.