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Published on: November 30, 2013
Epigenetic Regulation of VCAM-1 by Lipoxin A4 Is Renoprotective Against Diabetic Kidney Disease
Madhura Bose1, Muthukumar Mohan1, Jun Okabe2
1Department of Diabetes, Monash University, Melbourne, Australia.
Abstract:
Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α-induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells.
Article Highlights:
Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene.
Insights
Lipoxins (LXs) reduce inflammation and protect kidneys in diabetic kidney disease (DKD). They work by epigenetically modifying the VCAM-1 gene, offering a novel therapeutic approach for DKD.
Area of Science:
- Nephrology
- Immunology
- Epigenetics
Background:
- Diabetic kidney disease (DKD) is linked to chronic inflammation.
- Lipoxins (LXs) are lipid mediators that resolve inflammation and protect against renal scarring.
- The precise mechanism of LX action in DKD is not fully understood.
Purpose of the Study:
- To investigate how LXs protect against DKD.
- To examine the regulation of VCAM-1 and macrophage recruitment by LXs.
- To elucidate the epigenetic mechanisms involved in LX-mediated renoprotection.
Main Methods:
- Diabetic ApoE knockout mice models were used for in vivo studies.
- In vitro studies were conducted on human and mouse renal cell populations.
- LXA4 and its mimetics were assessed for their effects on VCAM-1 expression and epigenetic modifications.
Main Results:
- LXs attenuated albuminuria, mesangial expansion, and extracellular matrix deposition in experimental DKD.
- LXs reduced TNF-α-induced VCAM-1 expression in renal cells.
- Renoprotection was partly mediated by LX-induced H3K4 monomethylation of the VCAM-1 gene promoter.
Conclusions:
- LXs protect against DKD by modulating glomerular endothelial cell inflammation.
- A novel epigenetic mechanism involving H3K4 monomethylation of the VCAM-1 gene contributes to LX-mediated renoprotection.
- LXs represent a promising therapeutic strategy for managing DKD.
