Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy.

Kidney international 2021 Jul

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Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy. Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Citation

Liang Wu, Changjie Liu, Dong-Yuan Chang, Rui Zhan, Jing Sun, Shi-He Cui, Sean Eddy, Viji Nair, Emily Tanner, Frank C Brosius, Helen C Looker, Robert G Nelson, Matthias Kretzler, Jian-Cheng Wang, Ming Xu, Wenjun Ju, Ming-Hui Zhao, Min Chen, Lemin Zheng. Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy. Kidney international. 2021 Jul;100(1):107-121