4.7 Article

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

期刊

KIDNEY INTERNATIONAL
卷 100, 期 1, 页码 107-121

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2021.02.025

关键词

Ac2-26; annexin A1; diabetic nephropathy; proresolution

资金

  1. National Institutes of Health (NIH)-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  2. National Center for Advancing Translational Sciences
  3. NIH
  4. National Key Research and Development Program [2016YFC1305405]
  5. National Natural Science Foundation [82090021, 82070748, 91639108, 81770272, 81970425]
  6. Interdisciplinary Clinical Research Project of Peking University First Hospital
  7. University of Michigan Health System and Peking University Health Sciences Center Joint Institute for Translational and Clinical Research [BMU2017JI001]
  8. Peking University Medicine Seed Fund for Interdisciplinary Research [BMU2018MX025]
  9. Innovation Fund for Outstanding Doctoral Candidates of Peking University Health Science Center [71013Y2029]
  10. Applied Systems Biology Core at the University of Michigan George M. O'Brien Kidney Translational Core Center [P30 DK081943]
  11. Intramural Research Program of the NIDDK

向作者/读者索取更多资源

The study revealed that ANXA1 levels were upregulated in kidneys of diabetic nephropathy patients, correlating with kidney function and outcomes. ANXA1 deficiency exacerbated kidney injuries, while ANXA1 overexpression ameliorated the disease. The ANXA1 mimetic peptide Ac2-26 showed therapeutic potential for diabetic nephropathy.
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-kappa B 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.

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