Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Majumder, Syamantak; Thieme, Karina; Batchu, Sri Nagarjun; Alghamdi, Tamadher A.; Bowskill, Bridgit B.; Kabir, M. Golam; Liu, Youan; Advani, Suzanne L.; White, Kathryn; Geldenhuys, Laurette; Tennankore, Karthik; Poyah, Penelope; Siddiqi, Ferhan; Advani, Andrew

doi:10.1172/jci95946

Cited by 96 publications

(119 citation statements)

References 73 publications

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“…In our studies, we found that elevated KDM6A levels and reduced H3K27me3 levels, together with a significant decrease in nephrin, were consistently detected in podocytes in vitro and in vivo under hyperglycemic conditions. Our findings are generally consistent with the previous study by Majumder et al (), which showed the involvement of KDM6A in podocyte dedifferentiation. Besides, we here provide at least four additional pieces of information to further support the importance of KDM6A in promoting podocyte dysfunction.…”

Section: Discussionsupporting

confidence: 94%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 94%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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“…A chronic low dosage of GSK‐J4 decreases NFBG levels (Majumder et al . ), whereas no difference was observed in the present study (Table ). These results may indicate a direct effect of high dosage GSK‐J4 on DKD because lowering blood glucose usually attenuates multiple diabetic complications (Pirart et al .…”

Section: Discussioncontrasting

confidence: 83%

“…However, in that previous work, a low dosage of GSK‐J4 (10 mg kg −1 body weight, twice per week) was injected into 2‐month‐old male db/db mice, which had just become diabetic (Katharine P. Hummel, ), for 10 weeks for prevention purposes; although normalized renal function (as demonstrated by reduced albuminuria) and podocyte foot process effacement were achieved, there was no effect on podocyte loss and urine volume (Majumder et al . ). We thus hypothesize that other cell types may also contribute to the beneficial effects observed.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, an increased UTX level was reported in the podocytes of patients with DKD or focal segmental glomerulosclerosis, and UTX overexpression in cultured podocytes upregulates Jagged‐1, a ligand of Notch1 signalling, which is involved in podocyte de‐differentiation (Majumder et al . ). However, whether UTX plays additional roles in DKD remains unclear.…”

Section: Introductionmentioning

confidence: 97%

“…Because di-and tri-methylation of H3K27 are associated with gene silencing, upregulated UTX is usually associated with gene activation (Welstead et al 2012;Faralli et al 2016). Recently, an increased UTX level was reported in the podocytes of patients with DKD or focal segmental glomerulosclerosis, and UTX overexpression in cultured podocytes upregulates Jagged-1, a ligand of Notch1 signalling, which is involved in podocyte de-differentiation (Majumder et al 2018). However, whether UTX plays additional roles in DKD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity‐Related Properties

Yan

Fan

et al. 2021

Advanced Science

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The trimethylation on histone H3 lysine 27 (H3k27me3), a transcriptionally repressive epigenetic mark of permissive chromatin, can be removed by the histone lysine demethylase 6a (Kdm6a). However, the physiological function of H3k27me3 and Kdm6a on circadian genes remains largely elusive. With the ChIP-Seq and mRNA microarray assays, a critical role is identified for Kdm6a in the regulation of H3k27me3 to impact the expression of Crytochrome 1 (Cry1) in the hypothalamus of diet induced obesity mice. More importantly, both conditional knockout and pharmacological inhibition of Kdm6a reduce body weight and stabilize blood glucose homeostasis. Although a Kdm6a inhibitor fails to decrease body weight in leptin receptor-deficient db/db mice, it significantly decreases Cry1 expression, enhances sensitivity to exogenous leptin administration, and blocks body weight increases in endo-leptindeficient ob/ob mice. Moreover, gene analysis of the human hypothalamus further reveals a positive correlation between Kdm6a and Cry1. The results show that inhibition of Kdm6a reduces the Cry1 expression and sensitizes leptin signaling to combat obesity-related disease. Therefore, it implicates Kdm6a as an attractive drug target for obesity and metabolic disorders.

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Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Cited by 96 publications

References 73 publications

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity‐Related Properties

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