Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation

Hui-fang Zhang1,2,3, Hui-ming Liu4,5, Jia-yi Xiang1,2,3, Xing-cheng Zhou1,2,3, Dan Wang1,2,3, Rong-yu Chen1,2,3, Wan-lin Tan1,2, Lu-qun Liang1,2,3, Ling-ling Liu1,2,3, Ming-jun Shi1,2,3, Fan Zhang1,2,3, Ying Xiao1,2,3, Yu-xia Zhou1,2,3, Tian Zhang1,2,3, Lei Tang4,6, Bing Guo1,2,3, Yuan-yuan Wang2,3,4
1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China
2 International Scientific and Technological Cooperation Base of Pathogenesis and Drug Research on Common Major Diseases, Guizhou Medical University, Guiyang 550025, China
3 Department of Pathophysiology, Guizhou Medical University, Guiyang 550025, China
4 Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang 550025, China
5 Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
6 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550025, China
Correspondence to: Lei Tang:, Bing Guo:, Yuan-yuan Wang:,
DOI: 10.1038/s41401-022-00997-1
Received: 20 April 2022
Accepted: 6 September 2022
Advance online: 8 November 2022


Previous studies have shown mitochondrial dysfunction in various acute kidney injuries and chronic kidney diseases. Lipoic acid exerts potent effects on oxidant stress and modulation of mitochondrial function in damaged organ. In this study we investigated whether alpha lipoamide (ALM), a derivative of lipoic acid, exerted a renal protective effect in a type 2 diabetes mellitus mouse model. 9-week-old db/db mice were treated with ALM (50 mg·kg−1·d−1, i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels in db/db mice, but restored renal function and significantly improved fibrosis of kidneys. We demonstrated that ALM administration significantly ameliorated mitochondrial dysfunction and tubulointerstitial fibrotic lesions, along with increased expression of CDX2 and CFTR and decreased expression of β-catenin and Snail in kidneys of db/db mice. Similar protective effects were observed in rat renal tubular epithelial cell line NRK-52E cultured in high-glucose medium following treatment with ALM (200 μM). The protective mechanisms of ALM in diabetic kidney disease (DKD) were further explored: Autodock Vina software predicted that ALM could activate RXRα protein by forming stable hydrogen bonds. PROMO Database predicted that RXRα could bind the promoter sequences of CDX2 gene. Knockdown of RXRα expression in NRK-52E cells under normal glucose condition suppressed CDX2 expression and promoted phenotypic changes in renal tubular epithelial cells. However, RXRα overexpression increased CDX2 expression which in turn inhibited high glucose-mediated renal tubular epithelial cell injury. Therefore, we reveal the protective effect of ALM on DKD and its possible potential targets: ALM ameliorates mitochondrial dysfunction and regulates the CDX2/CFTR/β-catenin signaling axis through upregulation and activation of RXRα.
Keywords: diabetic kidney disease; alpha lipoamide; mitochondria; RXRα; CDX2; tubulointerstitial fibrosis

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