Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Dapagliflozin relieves renal injury in a diabetic nephropathy model by inducing autophagy through regulation of miR-30e-5p/AKT/mTOR pathway

Jun Zhang¹ , Ting Ding¹, Ximei Zhang¹, Dongxing Tang¹, Jianping Wang²

¹Department of Nephropathy and Rheumatism and Hunan Province End Stage Renal Disease, Clinical Medical Research Center, Second Affiliated Hospital, Hengyang Medical School of University of South China, Hengyang, Hunan Province 421001, China; ²Department of Endocrine, Second Affiliated Hospital, Hengyang Medical School of University of South China, Hengyang, Hunan Province 421001, China.

For correspondence:- Jun Zhang Email: zhangjun_911@163.com Tel:+867348899699

Accepted: 26 September 2022 Published: 28 October 2022

Citation: Zhang J, Ding T, Zhang X, Tang D, Wang J. Dapagliflozin relieves renal injury in a diabetic nephropathy model by inducing autophagy through regulation of miR-30e-5p/AKT/mTOR pathway. Trop J Pharm Res 2022; 21(10):2115-2123 doi: 10.4314/tjpr.v21i10.11

© 2022 The authors.
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Abstract

Purpose: To investigate the mechanism of action of dapagliflozin on diabetic nephropathy.

Methods: A rat model of diabetic nephropathy was established by injection of fructose-streptozotocin. Blood glucose and urinary protein levels were measured, while histopathological changes in kidney tissues were determined by hematoxylin & eosin staining (H & E). Serum levels of creatinine (Cr), blood urea nitrogen (BUN), malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), and lactate dehydrogenase (LDH) were evaluated by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis and autophagy were investigated by evaluating apoptotic and autophagic protein expression by western blot.

Results: Administration of fructose-streptozotocin increased the blood glucose level of the rats (p < 0.001) and induced pathological changes in the kidney tissues, including glomerulosclerosis, renal tubule dilation, and inflammatory cell infiltration of rats. However, long-term treatment with dapagliflozin attenuated the fructose-streptozotocin-induced increases in Cr, BUN, and urinary protein and reversed the fructose-streptozotocin-induced decrease in Bcl-2 expression and increases in Bax and cleaved PARP expression in diabetic rats. Dapagliflozin also reversed the increases in MDA and LDH and decreases in SOD and GSH in diabetic rats. The fructose-streptozotocin-induced increase in p62 expression and decreases in LC3 and Beclin 1 expression were reversed by dapagliflozin. It upregulated miR-30e-5p expression and downregulated phosphorylated AKT and mTOR expression in diabetic rats. MicroRNA-30e-5p targeted AKT and inhibition of miR-30e-5p attenuated the dapagliflozin-induced decrease in p-AKT and p-mTOR expression in diabetic rats.

Conclusion: In fructose-streptozotocin-induced diabetic rats, dapagliflozin ameliorates kidney injury, suppresses cell apoptosis and oxidative stress, and promotes cell autophagy through upregulation of miR-30e-5p and inactivation of the AKT/mTOR pathway. Therefore, dapagliflozin is a potent therapeutic agent for the management of diabetic neuropathy.

Keywords: Dapagliflozin, Apoptosis, Oxidative stress, Autophagy, Diabetic nephropathy, Fructose-streptozotocin