Statins play an important role in the treatment of diabetic nephropathy. Increasing attention has been given to the relationship between statins and insulin resistance, but many randomized controlled trials confirm that the therapeutic effects of statins on diabetic nephropathy are more beneficial than harmful. However, further confirmation of whether the beneficial effects of chronic statin administration on diabetic nephropathy outweigh the detrimental effects is urgently needed. Here, we find that long-term statin administration may increase insulin resistance, interfere with lipid metabolism, leads to inflammation and fibrosis, and ultimately fuel diabetic nephropathy progression in diabetic mice. Mechanistically, activation of insulin-regulated phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway leads to increased fatty acid synthesis. Furthermore, statins administration increases lipid uptake and inhibits fatty acid oxidation, leading to lipid deposition. Here we show that long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.

Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.

Objective: This study describes the expression profiles and roles of cardiac pigment epithelium-derived factor (PEDF) during cardiac development. Methods: Gene datasets from the Gene Expression Omnibus (GEO) database were used to analyze the correlation between cardiac PEDF expression and heart disease. Western blotting, immunohistochemistry, histological staining and echocardiography were used to assess the expression patterns and functions of PEDF during cardiac development. Results: Analysis of GEO data sets indicated that the expression of cardiac PEDF correlated with the occurrence and development of various heart diseases. Western blotting of various tissues in mice at 30 postnatal days of age indicated higher PEDF expression in the heart and aorta than the liver. Immunohistochemical results demonstrated that the expression of cardiac PEDF significantly decreased after birth, mainly because of a significant decrease in PEDF expression in the cytoplasm. Histological staining and echocardiography indicated that PEDF deficiency had no significant effects on cardiac structure, cardiac function and vascular hemodynamics in 8-week-old mice. Conclusion: Cardiac PEDF shows high expression and dynamic changes during cardiac development, but has no effects on cardiac structure, function and vascular hemodynamics.