Epigenetic regulation of VCAM-1 by Lipoxin A4 is renoprotective against diabetic kidney disease

Chronic low-grade inflammation underlies many microvascular complications of diabetes, including in diabetic kidney disease (DKD). Lipoxins (LX), 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, focussing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. Lipoxin A4 (LXA4) and two fourth generation mimetics were assessed in diabetic ApoE KO 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 preventative and delayed intervention in experimental DKD. LXs also attenuated the TNF-α-induced expression of inflammatory markers with VCAM-1 gene expression consistently reduced in all renal cell populations. Further analysis identified the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, that did not appear to be dependent on NFkB 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.