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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)107-121
Number of pages15
JournalKidney International
Volume100
Issue number1
DOIs
StatePublished - Jul 2021

Keywords

  • Ac2-26
  • annexin A1
  • diabetic nephropathy
  • proresolution

ASJC Scopus subject areas

  • Nephrology

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