2. Academic Validation
  3. Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation

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

  • Acta Pharmacol Sin. 2022 Nov 8. doi: 10.1038/s41401-022-00997-1.
Hui-Fang Zhang # 1 2 3,  Hui-Ming Liu # 4 5,  Jia-Yi Xiang 1 2 3,  Xing-Cheng Zhou 1 2 3,  Dan Wang 1 2 3,  Rong-Yu Chen 1 2 3,  Wan-Lin Tan 1 2,  Lu-Qun Liang 1 2 3,  Ling-Ling Liu 1 2 3,  Ming-Jun Shi 1 2 3,  Fan Zhang 1 2 3,  Ying Xiao 1 2 3,  Yu-Xia Zhou 1 2 3,  Tian Zhang 1 2 3,  Lei Tang 6 7,  Bing Guo 8 9 10,  Yuan-Yuan Wang 11 12 13
Affiliations

Affiliations

  • 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 Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China. tlei1974@163.com.
  • 7 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, China. tlei1974@163.com.
  • 8 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550025, China. Guobingbs@126.com.
  • 9 International Scientific and Technological Cooperation Base of Pathogenesis and Drug Research on Common Major Diseases, Guizhou Medical University, Guiyang, 550025, China. Guobingbs@126.com.
  • 10 Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China. Guobingbs@126.com.
  • 11 International Scientific and Technological Cooperation Base of Pathogenesis and Drug Research on Common Major Diseases, Guizhou Medical University, Guiyang, 550025, China. Yuan.yuan.wang@outlook.com.
  • 12 Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China. Yuan.yuan.wang@outlook.com.
  • 13 Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China. Yuan.yuan.wang@outlook.com.
  • # Contributed equally.
PMID: 36347997 DOI: 10.1038/s41401-022-00997-1
Abstract

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. Schematic figure illustrating that ALM alleviates diabetic kidney disease by improving mitochondrial function and upregulation and activation of RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on β-catenin activation and nuclear translocation. RTEC renal tubular epithelial cell. ROS Reactive Oxygen Species. RXRα Retinoid X receptor-α. Mfn1 Mitofusin 1. Drp1 dynamic-related protein 1. MDA malondialdehyde. 4-HNE 4-hydroxynonenal. T-SOD Total-superoxide dismutase. CDX2 Caudal-type homeobox transcription factor 2. CFTR Cystic fibrosis transmembrane conductance regulator. EMT epithelial mesenchymal transition. α-SMA Alpha-smooth muscle actin. ECM extracellular matrix. DKD diabetic kidney disease. Schematic figure was drawn by Figdraw ( www.figdraw.com ).

Keywords

CDX2; RXRα; alpha lipoamide; diabetic kidney disease; mitochondria; tubulointerstitial fibrosis.

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