Abstract
Atorvastatin is a classical lipid-lowering drug. It has been reported to have renoprotective effects, such as reducing urinary protein excretion and extracellular matrix aggregation. The present study aimed to investigate the specific mechanism of action of Atorvastatin in type 1 diabetic mice (T1DM) in inhibiting renal tubular epithelial cell injury following treatment with high glucose and high fat. The anti-injury mechanism of Atorvastatin involved the inhibition of miR-21 expression and the upregulation of the transcription and expression of its downstream gene Peroxisome proliferator-activated receptors-α(PPARα). An increase in blood glucose and lipid levels was noted in the T1DM model, which was associated with renal fibrosis and inflammation. These changes were accompanied by increased miR-21 levels, downregulation of PPARα and Mfn1 expressions, and upregulation of Drp1 and IL6 expressions in renal tissues. These phenomena were reversed following the administration of Atorvastatin. miR-21 targeted PPARα by inhibiting its mRNA translation. Inhibition of miR-21 expression or Fenofibrate (PPARα agonist) administration prevented the decrease of PPARα in renal tubular epithelial cells under high glucose (HG) and high fat (Palmitic acid, PA) conditions, alleviating lipid metabolism disorders and reducing mitochondrial dynamics and inflammation. Consistent with the in vivo results, the in vitro findings also demonstrated that mRTECs administered with Atorvastatin in HG + PA increased PPARα expression and restored the normal expression of Mfn1 and Drp1, and effectively increasing the number of biologically active mitochondria and ATP content, reducing ROS production, and restoring mitochondrial membrane potential following Atorvastatin intervention. In addition, these effects were noted to the inhibition of FN expression and tubular cell inflammatory response; however, in the presence of miR-21mimics, the aforementioned effects of Atorvastatin were significantly diminished. Based on these observations, we conclude that Atorvastatin inhibits tubular epithelial cell injury in T1DM with concomitant induction of lipid metabolism disorders by a mechanism involving inhibition of miR-21 expression and consequent upregulation of PPARα expression. Moreover, Atorvastatin regulated lipid metabolism homeostasis and PPARα to restore mitochondrial function. The results emphasize the potential of Atorvastatin to exhibit lipid-regulating functions and non-lipid effects that balance mitochondrial dynamics.
Highlights
In 2019, the International Diabetes Federation (IDF) predicted that the global prevalence of diabetes will be 9.3% (463 million people)
The mice treated with Atorvastatin [20 mg/(kgd)] for 4 weeks indicated no significant change in blood glucose levels (Figure 1A), whereas a significant decrease was noted in urea nitrogen and creatinine levels, as well as in the incidence of microalbuminuria (Figures 1B–D)
These findings suggest that both high-glucose or highfat environments cause downregulation of Peroxisome proliferator-activated receptor-α (PPARα) expression, impair mitochondrial function, and promote the expression of inflammatory factors and fibronectin to mediate renal tubular injury. In contrast to these findings, miR-21 inhibitor and Fenofibrate both upregulated PPARα expression, which in turn restored the expression levels of proteins affecting mitochondrial function and reversed the inflammatory response and fibrosis progression in renal tubular epithelial cells induced by hyperglycemia and hyperlipidemia. These results suggested that miR-21 may contribute to high glucose or high fatinduced renal tubular epithelial cell injury by downregulating PPARα expression leading to impaired mitochondrial function and lipid metabolism disorders
Summary
In 2019, the International Diabetes Federation (IDF) predicted that the global prevalence of diabetes will be 9.3% (463 million people). This incidence is predicted to rise to 10.2% (578 million people) by 2030 and to 10.9% (700 million people) by 2045. As one of the most common microvascular complications of diabetes, diabetic nephropathy (DN) is a major cause of the end-stage renal disease (ESRD) (Saeedi et al, 2019). Diabetic kidney disease (DKD) has been a difficult clinical problem to treat, and intensive glycemic control can only reduce but not eradicate the progression of the disease. It has been found that patients with diabetes mellitus usually have abnormal glucose metabolism along with abnormal lipid metabolism. Dyslipidemia is a significant risk factor for the development of DN (HermanEdelstein et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
