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The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism through AMPK/PPARα/CPT1b Pathway

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posted on 09.07.2021, 21:28 by Liang Wu, Changjie Liu, Dong-Yuan Chang, Rui Zhan, Mingming Zhao, Sin Man Lam, Guanghou Shui, Ming-Hui Zhao, Lemin Zheng, Min Chen
Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. Here, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA), and explore the association of ANXA1 with lipid accumulation in DN patients. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion and tubulointerstitial lesions in HFD/STZ-induced diabetic mice. ANXA1 deficiency promotes intra-renal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, ANXA1 silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr172AMPK, resulting in decreased PPARα and CPT1b expression and increased HGPA-induced lipid accumulation, apoptosis and elevated expression of pro-inflammatory and pro-fibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of DN patients. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression, hence it holds great potential as a therapeutic target for DN.

Funding

This study was funded by grants from the National Key Research and Development Program (No. 2016YFC1305405), grants from the National Natural Science Fund (No. 82090020, 82090021, 82070748, 91639108, 81770272 and 81970425), a grant from CAMS Innovation Fund for Medical Sciences (2019-I2M-5-046), and a grant by the University of Michigan Health System, and Peking University Health Sciences Center Joint Institute for Translational and Clinical Research (No. BMU2017JI001).

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