Dl-3-n-Butylphthalide Ameliorates Diabetic Nephropathy by Ameliorating Excessive Fibrosis and Podocyte Apoptosis

Jingyu Xu; Zonghao Tang; Youwu He; Shufang Cai; Beini Wang; Susu Zhang; Man Wu; Kai Qian; Kailun Zhang; Bo Chai; Guorong Chen; Ke Xu; Hao Ji; Jian Xiao; Yanqing Wu

doi:10.3389/fphar.2021.628950

Dl-3-n-Butylphthalide Ameliorates Diabetic Nephropathy by Ameliorating Excessive Fibrosis and Podocyte Apoptosis

Front Pharmacol. 2021 Aug 23:12:628950. doi: 10.3389/fphar.2021.628950. eCollection 2021.

Authors

Jingyu Xu¹, Zonghao Tang², Youwu He³, Shufang Cai¹, Beini Wang⁴, Susu Zhang⁴, Man Wu⁴, Kai Qian¹, Kailun Zhang¹, Bo Chai⁴, Guorong Chen⁵, Ke Xu¹, Hao Ji¹, Jian Xiao⁴, Yanqing Wu¹

Affiliations

¹ The Institute of Life Sciences, Wenzhou University, Wenzhou, China.
² Drug Discovery Research Center, Key Laboratory of Medical Electrophysiology of Ministry of Education, Southwest Medical University, Luzhou, China.
³ Department of hand and plastic surgery, The First People's Hospital of Yuhang District, Hangzhou, China.
⁴ Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
⁵ Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mg⋅kg^-1 d^-1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mg⋅kg^-1 d^-1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.

Keywords: diabetic nephropathy; dl-3-n-butylphthalide; endoplasmic reticulum stress; glomerular filtration barrier; podocytes; vascular endothelial growth factor.