High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells

• DOI: 10.1074/jbc.m115.651604
• Publication Date: 2015-07-15T00:30:20Z
• Authors: Renzhong Li; Lalita Uttarwar; Bo Gao; Martine Charbonneau; Yixuan Shi; John S.D. Chan; Claire M. Dubois; Joan C. Krepinsky
• Keywords: Mesangial cell

We previously showed that ADAM17 mediates high glucose-induced matrix production by kidney mesangial cells. expression is increased in diabetic kidneys, suggesting its up-regulation may augment glucose profibrotic responses. thus studied the effects of on gene regulation. Primary rat cells were treated with (30 mm) or mannitol as osmotic control. High dose-dependently promoter activity, transcript, and protein levels. This correlated augmented activity after 24 h versus 1 glucose. tested involvement transcription factors shown other settings to regulate transcription. Promoter activation was not affected NF-κB Sp1 inhibitors, but blocked hypoxia-inducible factor-1α (HIF-1α) inhibition down-regulation. also prevented transcript increases. HIF-1α nuclear translocation HIF-responsive hypoxia-response element (HRE)-luciferase reporter construct. Assessment deletion constructs coupled mutation analysis ChIP studies identified binding consensus at -607 critical for response. Finally, inhibitors epidermal growth factor receptor (EGFR) downstream PI3K/Akt, itself, up-regulation. Thus, induces transcriptional cells, which associated augmentation activity. mediated requires EGFR/ADAM17 signaling, demonstrating potentiation own provides a potential novel therapeutic strategy treatment nephropathy.