Supplementary material v2.pdf (4.14 MB)
The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism through AMPK/PPARα/CPT1b Pathway
figure
posted on 2021-07-09, 21:28 authored by Liang Wu, Changjie Liu, Dong-Yuan Chang, Rui Zhan, Mingming Zhao, Sin Man Lam, Guanghou Shui, Ming-Hui Zhao, Lemin Zheng, Min ChenInflammation 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.