👤 Catherine Godson

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. 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. Show less

Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM. Show less