A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

Abstract

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.

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

“…In addition, prolonged treatment with TAK-418 may have broader impacts on the epigenetic cross-talk mechanism beyond H3K4 and H3K9 methylation. For example, chronic TAK-418 treatment altered the expression of Klf10 [known to increase the expression of the histone lysine demethylase KDM6A (lysine demethylase 6A) ( 20 )] and Sgk1 [known to phosphorylate and suppress the activity of the lysine methyltransferase KMT2D (lysine methyltransferase 2D) ( 21 )] in the 5-week-old VPA rats (table S3). During the 14-day TAK-418 treatment period, such epigenetic modifications would repeatedly and dynamically occur in multiple genes, responding to the expression status.…”

Combination CTLA-4 immunoglobulin treatment and ultrasound microbubble-mediated exposure improve renal function in a rat model of diabetic nephropathy

“…Nephrin and podocin are podocyte-specific markers, the expression of which is significantly reduced in diabetic podocytes [ 39 – 41 ]. Proteinuria and DN are correlated with the reduced expression of nephrin and podocin [ 42 ].…”

De-Glycyrrhizinated Licorice Extract Attenuates High Glucose-Stimulated Renal Tubular Epithelial–Mesenchymal Transition via Suppressing the Notch2 Signaling Pathway

“…Western blot analysis was performed as described previously [25]. In brief, protein lysates of cultured cells were prepared using tissue protein extraction reagent (Pierce, Rockford, IL, USA) according to the manufacture's instruction.…”

“…, and analysis of quantitative PCR data were performed as mentioned previously [25]. The PCR primers used are following: 5 -GTCTGCAAAGAAGGCTGGGA and 5 -GCCACACCAGACCTTGGAGC for Jagged-1;…”