The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation

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標題:	The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation
作者:	Hung, Peir-Haur Hsu, Yung-Chien Chen, Tsung-Hsien Ho, Cheng Lin, Chun-Liang
貢獻者:	Chia Nan University of Pharmacy & Science Chang Gung Memorial Hospital Chang Gung Memorial Hospital Chang Gung Memorial Hospital Chang Gung Memorial Hospital Chang Gung Memorial Hospital
關鍵字:	growth-factor-beta hyperglycemia phosphorylation inflammation mechanisms dickkopf-1 matrix cells jnk emt
日期:	2022
上傳時間:	2023-12-11 14:00:26 (UTC+8)
出版者:	MDPI
摘要:	Diabetic kidney disease (DKD) can cause inflammation and fibrosis, in addition to being the main complication of diabetes. Among many factors, epigenetic alterations in aberrant histone modifications play a key role in causing DKD. In this study, the mechanism of GSK-J4, a histone demethylase KDM6A inhibitor, was evaluated in streptozotocin-induced diabetic mice. It was confirmed that GSK-J4, via dickkopf-1 (DKK1) modulation, could significantly reduce proteinuria and glomerulosclerosis in diabetic mice. The mRNA accumulation levels of DKK1, TGF-beta 1, fibronectin, and collagen IV were significantly elevated in diabetic mice. In contrast, the mRNA accumulations of those genes were significantly reduced in diabetic mice treated with GSK-J4 compared to those in diabetic mice, relatively speaking. The protein accumulation levels of fibronectin and collagen IV were significantly elevated in diabetic mice. Furthermore, GSK-J4 attenuated the high glucose-induced expression of profibrotic factors in mesangial cells via DKK1. In conclusion, our study provides a novel strategy to eliminate fibrosis in the kidneys of DKD mice. Using GSK-J4 reduces DKK1 expression, thereby ameliorating renal insufficiency, glomerulosclerosis morphological abnormalities, inflammation, and fibrosis in diabetic mice.
關聯:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.23, n.CB2, pp.CC2, pp.-,
显示于类别:	[行政單位] 123

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