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

Abstract

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. In this study, 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 patients with DN. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion, and tubulointerstitial lesions in high-fat diet/streptozotocin-induced diabetic mice. ANXA1 deficiency promotes intrarenal 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 Thr172 AMPK, resulting in decreased peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1b expression and increased HGPA-induced lipid accumulation, apoptosis, and elevated expression of proinflammatory and profibrotic 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 patients with DN. 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.

• Authors: Liang Wu, Changjie Liu, Dong-Yuan Chang, Rui Zhan, Mingming Zhao, Sin Man Lam, Guanghou Shui, Ming-Hui Zhao, Lemin Zheng, Min Chen
• Journal: Diabetes (Diabetes) Vol. 70 Issue 10 Pg. 2192-2203 (10 2021) ISSN: 1939-327X [Electronic] United States
• PMID: 34103347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by the American Diabetes Association.

Chemical References

• Annexin A1
• PPAR alpha
• Streptozocin
• CPT1B protein, human
• CPT1B protein, mouse
• Carnitine O-Palmitoyltransferase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Annexin A1 (genetics, physiology)
• Carnitine O-Palmitoyltransferase (genetics, metabolism)
• Case-Control Studies
• Cells, Cultured
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Diabetic Nephropathies (genetics, metabolism, pathology)
• Humans
• Lipid Metabolism (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha (genetics, metabolism)
• Signal Transduction (genetics)
• Streptozocin