Mineralocorticoid receptor antagonizes Dot1a-Af9 complex to increase<i>αENaC</i>transcription

Zhang, Xi; Zhou, Qiaoling; Chen, Lihe; Berger, Stefan; H, Wu; Xiao, Zhou; Pearce, David; Zhou, Xiaodong; Zhang, Wenzheng

doi:10.1152/ajprenal.00202.2013

Cited by 12 publications

(4 citation statements)

References 59 publications

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“…Aldosterone relieves this repression by downregulating Dot1a and Af9 expression and by stimulating Sgk1, which, in turn, phosphorylates Af9 at S435 to attenuate Dot1a-Af9 interaction [24]. MR antagonizes Dot1a-Af9 action by competing with Dot1a for binding Af9 [34]. Aldosterone-independent relief comes from the action of Af17.…”

Section: Discussionmentioning

confidence: 99%

Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Xiao

Chen

Zhou

et al. 2016

Experimental Cell Research

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The collecting duct in the mammalian kidney consists of principal cells (PCs) and intercalated cells (ICs), which regulate electrolyte/fluid and acid/base balance, respectively. The epigenetic regulators of PC and IC differentiation remain obscure. We previously used Aqp2 and V-ATPase B1B2 to label PCs and ICs, respectively. We found that mice with histone H3 K79 methyltransferase Dot1l disrupted in Aqp2-expressing cells (Dot1lAC) vs. Dot1lf/f possessed ~20% more ICs coupled with a similar decrease in PCs. Here, we performed multiple double immunofluorescence staining using various PC and IC markers and confirmed that this finding. Both α-IC and β-IC populations were significantly expanded in Dot1lAC vs. Dot1lf/f. These changes are associated with significantly upregulated V-ATPase B1 and B2, but not Aqp2, AE1, and Pendrin. Chromatin immunoprecipitation assay unveiled a significant reduction of Dot1l and H3K79 di-methylation bound at the Atp6v1b1 5′ flanking region. Overexpression of Dot1a significantly downregulated a stably-transfected luciferase reporter driven by the Atp6v1b1 promoter in IMCD3 cells. This downregulation was impaired, but not completely abolished when a methyltransferase-dead mutant was overexpressed. Taken together, our data suggest that Dot1l is a new epigenetic regulator of PC and IC differentiation and Atp6v1b1 is a new transcriptional target of Dot1l.

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Section: Discussionmentioning

confidence: 99%

Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Xiao

Chen

Zhou

et al. 2016

Experimental Cell Research

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“…Aldosterone regulates sodium reabsorption and water retention in the distal tubule of the nephron by binding MR which—like other nuclear hormone receptors—serves as a ligand-activated transcription factor. 9, 10 This well-characterized event leads to altered transcription of genes in distal tubule epithelial cells and, 11-15 https://paperpile.com/c/zmmQO9/f5Ac+OGHz+UBrI+a5HD+oGKK ultimately, sodium reabsorption. 16 Low sodium intake results in increased RAAS-mediated aldosterone signaling via MR, whereas excess sodium intake downregulates expression of a set of genes controlled by MR. With this well-established physiology in mind, we assayed cell-depleted urine samples collected under two conditions: 1) after four days on a low-sodium (20 mmol/day) diet (n = 18) and 2) after subsequent sodium infusion and consumption of a high salt meal (n = 17 of the same participants).…”

Section: Resultsmentioning

confidence: 99%

Human Urinary mRNA as a Biomarker of Cardiovascular Disease

Bazzell

Rainey

Auchus

et al. 2018

Circ Genom Precis Med.

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Background Messenger RNA in urine supernatant (US-mRNA) might encode information about renal and cardiorenal pathophysiology, including hypertension. However, whether the US-mRNA transcriptome reflects that of renal tissues and whether changes in renal physiology are detectable using US-mRNA is unknown. Methods We compared transcriptomes of human urinary extracellular vesicles and human renal cortex. To avoid similarities attributable to ubiquitously expressed genes, we separately analyzed ubiquitously expressed and highly kidney-enriched genes. To determine whether US-mRNA reflects changes in renal gene expression, we assayed cell-depleted urine for transcription factor activity of mineralocorticoid receptors (MR) using probe-based qPCR. The urine was collected from pre-hypertensive individuals (n=18) after four days on low-sodium diet to stimulate MR activity and again after suppression of MR activity via sodium infusion. Results In comparing this US-mRNA and human kidney cortex, expression of 55 highly kidney-enriched genes correlated strongly (rs=0.82), while 8,457 ubiquitously-expressed genes correlated moderately (rs=0.63). Standard renin-angiotensin-aldosterone system phenotyping confirmed the expected response to sodium loading. Ct values for MR-regulated targets (SCNN1A, SCNN1G, TSC22D3) changed after sodium loading, and MR-regulated targets (SCNN1A, SCNN1G, SGK1, and TSC22D3) correlated significantly with serum aldosterone and inversely with urinary sodium excretion. Conclusions RNA-Seq of urinary extracellular vesicles shows concordance with human kidney. Perturbation in human endocrine signaling (MR activation) was accompanied by changes in mRNA in urine supernatant. Our findings could be useful for individualizing pharmacological therapy in patients with disorders of mineralocorticoid signaling, such as resistant hypertension. More generally, these insights could be used to non-invasively identify putative biomarkers of disordered renal and cardiorenal physiology.

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“…Aldosterone also acts through the MR to promote α‐subunit expression through histone modifications. Activated MR disrupts the binding of disruption of telomeric silencing 1 (Dot1a) and ALL1‐fused gene from chromosome 9 protein (Af9) that form a repression complex that binds to or near the α‐subunit promoter (Zhang et al., 2013). The addition of HSD with aldosterone could not only cause changes in the architecture of the tubule, but also amplify these known mechanisms or act through a novel transcriptional pathway.…”

Section: Discussionmentioning

confidence: 99%

Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling

Mutchler,

Hasan,

Murphy

et al. 2024

The Journal of Physiology

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Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α‐subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC β‐ and γ‐subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+Cl− cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+], but the addition of high salt markedly attenuated the aldosterone‐dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC‐positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross‐sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC‐positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+. imageKey points Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake. Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron. Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit. Aldosterone and its associated decrease in blood [K+] lead to an increased expression of Na‐Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+]. Upstream kinase regulators and tubule remodelling do not explain these results.

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Mineralocorticoid receptor antagonizes Dot1a-Af9 complex to increaseαENaCtranscription

Cited by 12 publications

References 59 publications

Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Human Urinary mRNA as a Biomarker of Cardiovascular Disease

Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling

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