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

• Published in: International journal of molecular sciences Vol. 23; no. 16; p. 9407
• Main Authors: Hung, Peir-Haur, Hsu, Yung-Chien, Chen, Tsung-Hsien, Ho, Cheng, Lin, Chun-Liang
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 20.08.2022; MDPI
• Subjects: Abnormalities; Accumulation; Collagen; Collagen (type IV); Creatinine; Cytokines; Diabetes; Diabetes mellitus; diabetic kidney disease; Diabetic nephropathy; DKK1; Dkk1 protein; DNA methylation; Epigenetics; Fibronectin; Fibrosis; Glucose; histone demethylase; Histones; Hyperglycemia; Inflammation; Inhibitors; Kidney diseases; Kinases; Mesangial cells; mRNA; Proteins; Proteinuria; Renal insufficiency; Rodents; Streptozocin; streptozotocin-induced diabetic mice; Therapeutic targets; Transforming growth factor-b1; Tumor necrosis factor-TNF
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23169407

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-β1, 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.