High glucose induces platelet?￠????derived growth factor?￠????C via carbohydrate response element?￠????binding protein in glomerular mesangial cells

摘要

Persistent high concentration of glucose causes cellular stress and damage in diabetes via derangement of gene expressions. We previously reported high glucose activates hypoxia?￠????inducible factor?￠????1 ???± and downstream gene expression in mesangial cells, leading to an extracellular matrix expansion in the glomeruli. A glucose?￠????responsive transcription factor carbohydrate response element?￠????binding protein (ChREBP) is a key mediator for such perturbation of gene regulation. To provide insight into glucose?￠????mediated gene regulation in mesangial cells, we performed chromatin immunoprecipitation followed by DNA microarray analysis and identified platelet?￠????derived growth factor?￠????C (PDGF?￠????C) as a novel target gene of ChREBP. In streptozotocin?￠????induced diabetic mice, glomerular cells showed a significant increase in PDGF?￠????C expression; the ratio of PDGF?￠????C?￠????positive cells to the total number glomerular cells demonstrated more than threefold increase when compared with control animals. In cultured human mesangial cells, high glucose enhanced expression of PDGF?￠????C protein by 1.9?￠????fold. Knock?￠????down of ChREBP abrogated this induction response. Upregulated PDGF?￠????C contributed to the production of type IV and type VI collagen, possibly via an autocrine mechanism. Interestingly, urinary PDGF?￠????C levels in diabetic model mice were significantly elevated in a fashion similar to urinary albumin. Taken together, we hypothesize that a high glucose?￠????mediated induction of PDGF?￠????C via ChREBP in mesangial cells contributes to the development of glomerular mesangial expansion in diabetes, which may provide a platform for novel predictive and therapeutic strategies for diabetic nephropathy.