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

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).

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Fig. 1: ALM restored renal function and improved fibrosis of renal tubular epithelial cells in db/db mice.
Fig. 2: ALM intervention reduced renal fibrosis.
Fig. 3: ALM ameliorated mitochondrial dysfunction in renal tubular epithelial cells of db/db mice.
Fig. 4: ALM inhibited high glucose-mediated apoptosis in renal tubular epithelial cells.
Fig. 5: ALM upregulated and activated RXRα, which in turn upregulated CDX2.
Fig. 6: RXRα prevented hyperglycemia-associated renal tubular lesions by positively regulating CDX2 to suppress β-catenin activation.
Fig. 7: ALM upregulated and activated RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on β-catenin activation and nuclear translocation.
Fig. 8: ALM resisted high glucose-mediated phenotypic loss of renal tubular epithelial cells through upregulation of RXRα and CDX2.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82060141 and 81960141), Merit-based Funding for High-level Talent Innovation and Entrepreneurship in Guizhou Province [(2021)02], Science and Technology Top Talent Project of General Higher Education Institutions in Guizhou Province (Qianjiaohe KY [2021] 032).Schematic figure was drawn by Figdraw (www.figdraw.com).

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HFZ, HML, LT, BG, and YYW designed the experiments, interpreted the data, and wrote the manuscript; HFZ, HML, JYX, XCZ, WLT, LQL conducted the experiments; YXZ, DW, RYC, LLL, MJS, FZ, TZ, YX analyzed the data; and all authors contributed helpful suggestions for this manuscript.

Corresponding authors

Correspondence to Lei Tang, Bing Guo or Yuan-yuan Wang.

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Zhang, Hf., Liu, Hm., Xiang, Jy. et al. Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00997-1

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  • DOI: https://doi.org/10.1038/s41401-022-00997-1

Keywords

  • diabetic kidney disease
  • alpha lipoamide
  • mitochondria
  • RXRα
  • CDX2
  • tubulointerstitial fibrosis

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