Open AccessA KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction
Author(s) -
Lin ChunLiang,
Hsu YungChien,
Huang YuTing,
Shih YaHsueh,
Wang ChingJen,
Chiang WenChih,
Chang PeyJium
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809828
Subject(s) - podocyte , mechanism (biology) , diabetes mellitus , medicine , microbiology and biotechnology , endocrinology , kidney , biology , proteinuria , physics , quantum mechanics
Diabetic nephropathy is the leading cause of end‐stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM 6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up‐regulation of its downstream target KLF 10. Overexpression of KLF 10 in podocytes not only represses multiple podocyte‐specific markers including nephrin, but also conversely increases KDM 6A expression. We further show that KLF 10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM 6A or KLF 10 in mice significantly suppresses diabetes‐induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM 6A and KLF 10 proteins or mRNA s are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM 6A– KLF 10 feedback loop may be beneficial to attenuate diabetes‐induced kidney injury.