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ziemann-lipoxinsregulate-2018.pdf (2.43 MB)

Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease

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Version 2 2024-06-04, 15:42
Version 1 2018-08-31, 21:44
journal contribution
posted on 2024-06-04, 15:42 authored by EP Brennan, M Mohan, A McClelland, C Tikellis, Mark ZiemannMark Ziemann, A Kaspi, SP Gray, R Pickering, SM Tan, S Tasadaque Ali-Shah, PJ Guiry, A El-Osta, K Jandeleit-Dahm, ME Cooper, C Godson, P Kantharidis
Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE−/− mice treated with streptozotocin.Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1β, NF-κB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α–driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α.Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

History

Journal

Journal of the American Society of Nephrology

Volume

29

Pagination

1437-1448

Location

United States

ISSN

1046-6673

eISSN

1533-3450

Language

English

Publication classification

C Journal article, C1.1 Refereed article in a scholarly journal

Copyright notice

2018 by the American Society of Nephrology

Issue

5

Publisher

AMER SOC NEPHROLOGY