Atrasentan alleviates high glucose-induced podocyte injury by the microRNA-21/forkhead box O1 axis

Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. Atrasentan (Atr) has potential therapeutic values for DN. MicroRNAs (miRNAs) function as vital regulators in the pathophysiology of kidney diseases including DN. Our present study aimed to further explore whether Atr could alleviate kidney injury by regulating microRNA-21(miR-21)/forkhead box O1 (FOXO1) in DN mouse models and cell models. Blood glucose concentration and ACR ratio were determined by matching commercial kits. MiR-21 and FOXO1 mRNA level was measured by RT-qPCR assay. Protein levels of FOXO1, LC3Ⅰ, LC3Ⅱ and p62 were measured by western blot assay. Cell apoptotic index was examined by flow cytometry. The interaction of miR-21 and FOXO1 was tested by bioinformatics analysis, luciferase assay and RIP assay. We found that Atr alleviated kidney injury by inhibiting miR-21 expression and promoting autophagy in DN mice. Moreover, miR-21 loss suppressed apoptosis and induced autophagy in high glucose (HG)-treated podocytes. And, Atr inhibited cell apoptosis and improved cell autophagic activity by downregulating miR-21 in HG-cultured podocytes. Moreover, FOXO1 was identified as a target of miR-21. MiR-21 exerted its pro-apoptosis and anti-autophagy effects by targeting FOXO1 in HG-cultured podocytes. Atr enhanced FOXO1 expression by downregulating miR-21 in HG-cultured podocytes. We concluded that Atr mitigated kidney injury in DN mice and alleviated HG-mediated apoptosis increase and autophagy inhibition in podocytes by regulating miR-21/FOXO1 axis, further elucidating the molecular basis by which Atr hampered DN progression.