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Supplementary Material for: Inhibitor of Differentiation 3, a Transcription Factor, Regulates Hyperlipidemia-Associated Kidney Disease
<p><b><i>Background:</i></b> 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 <i>Id3</i> in spontaneously hyperlipidemic apolipoprotein E knockout (<i>Apoe</i><sup><i>-/-</i></sup>)
mice led to accelerated mesangioproliferative glomerulonephritis. The
present study was carried out to further investigate the contribution of
ID3 in hyperlipidemia-associated kidney disease. <b><i>Methods:</i></b> Female C57BL/6 mice that were ID3-sufficient wild-type (WT) or ID3-deficient (<i>Id3</i><sup><i>-/-</i></sup>)
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. <b><i>Results:</i></b><i>Id3</i><sup><i>-/-</i></sup>
mice on a Western diet developed accelerated proteinuria and
mesangioproliferative glomerulonephritis compared to WT controls. In
vitro, <i>Id3</i><sup><i>-/-</i></sup> 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 <i>Id3</i><sup><i>-/-</i></sup> mice fed a Western diet. <b><i>Conclusions:</i></b>
A functional ID3 influences susceptibility to kidney disease and
prevents glomerular injury by regulating local chemokine production and
inflammatory cell recruitment.</p