Background: Lipoprotein abnormalities are associated with a rapid decline in renal function in patients of chronic kidney disease. In addition, hyperlipidemia is associated with an increased risk of developing renal insufficiency. The underlying molecular mechanisms for these clinical findings are unclear. We have previously reported a role for inhibitor of differentiation 3 (ID3), a transcription factor, in regulating kidney disease in hyperlipidemia. Introducing a genetic deficiency of Id3 in spontaneously hyperlipidemic apolipoprotein E knockout (Apoe-/-) mice led to accelerated mesangioproliferative glomerulonephritis. The present study was carried out to further investigate the contribution of ID3 in hyperlipidemia-associated kidney disease. Methods: Female C57BL/6 mice that were ID3-sufficient wild-type (WT) or ID3-deficient (Id3-/-) were fed a Western diet and evaluated for proteinuria, glomerular pathology, and immune infiltrating cells. 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. Glomerular isolates were studied for CXCL1 expression by QPCR. Results:Id3-/- mice on a Western diet developed accelerated proteinuria and mesangioproliferative glomerulonephritis compared to WT controls. In vitro, Id3-/- glomerular mesangial cell lines produced higher levels of the monocyte chemoattractant CXCL1 in response to oxidized phospholipids. This was consistent with the rapid increase in glomerular CXCL1 expression followed by macrophage infiltration in Id3-/- mice fed a Western diet. Conclusions: A functional ID3 influences susceptibility to kidney disease and prevents glomerular injury by regulating local chemokine production and inflammatory cell recruitment.

Journal Section:
Original Paper
Keywords:
Inhibitor of differentiation 3, Transcription factor, Hyperlipidemia-associated kidney disease
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