Background/Purpose: Responses of renal cells to pathogenic stimuli play an important role in dictating susceptibility to kidney disease.  Inhibitor of differentiation 3, ID3, is a member of the basic helix loop helix transcription factor family and is expressed in multiple cell types including glomerular mesangial cells.  We have previously reported that a genetic deficiency of ID3, leads to mesangio-proliferative glomerulonephritis in spontaneously hyperlipidemic Apolipoprotein E knockout (Apoe^-/-) mice. In the present study, we investigated the mechanisms of ID3 related glomerular disease in hyperlipidemia and studied its relevance in humans. Influence of ID3 on immune mediated glomerulonephritis was also studied.

Methods:

To study whether ID3 deficiency was sufficient for hyperlipidemic glomerulonephritis, C57BL/6 mice that were either ID3 sufficient wild type (WT) or ID3 deficient (Id3^-/- ) mice were fed a high fat western diet and evaluated for different parameters of kidney disease. To investigate the potential mechanism of action, primary mesangial cell lines were generated from both mouse strains and stimulated with oxidized phospholipids. Cytokines and chemokines produced were measured by multiplex assays, ELISA, and QPCR.  To study the relevance of ID3 in human disease, the association between ID3 single nucleotide polymorphisms (SNPs) and kidney disease was studied in participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and the influence of dyslipidemia on this association was investigated.  As an additional model of kidney disease, WT and Id3^-/- mice were injected with sheep anti-mouse glomerular basement membrane serum to induce immune mediated glomerular injury, and development of proteinuria was studied.

Results:

Id3^-/- mice on a western diet developed accelerated proteinuria and mesangio-proliferative glomerulonephritis. In vitro, Id3^-/- glomerular mesangial cell lines produced higher levels of the monocyte chemoattractant, CXCL1 in response to oxidized phospholipids compared to WT controls. This was consistent with the rapid increase in glomerular CXCL1 expression followed by glomerular macrophage infiltration in Id3^-/- mice fed a western diet. In humans, an analysis of MESA participants across three ethnic groups showed that of six tagging ID3 SNPs, the T allele of a non-synonymous, functional SNP rs11574 showed a significant association with decreased urinary albumin creatinine ratios in Caucasians (P=0.012). This association was even stronger in participants carrying small low density lipoprotein particles (p=0.0024).  This suggests the hypothesis that in the presence of lipid abnormalities, a change in ID3 influences kidney disease.  The significance of functional ID3 in other forms of glomerular injury of kidney disease was further demonstrated in immune mediated nephrotoxic nephritis where Id3^-/- mice developed severe and sustained proteinuria compared to WT mice.

 

Conclusion:

A functional ID3 may regulate susceptibility to kidney disease and prevent glomerular injury by regulating local chemokine production and inflammatory cell recruitment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibitor-of-differentiation-3-a-transcription-factor-regulates-susceptibility-to-kidney-disease/