Potassium acts through mTOR to regulate its own secretion

Sørensen, Mads Vaarby; Saha, Biswarup; Jensen, Iben; Wu, Peng; Ayasse, Niklas; Gleason, Catherine E.; Svendsen, Samuel L.; Wang, Wenhui; Pearce, David

doi:10.1172/jci.insight.126910

Cited by 50 publications

(101 citation statements)

References 56 publications

(87 reference statements)

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“…The changes in these transport proteins were similar to those seen after a chronic dietary K + challenge and it can be speculated that these changes rely on elevated K + concentration where modest increase or no change in ROMK was observed (28,42,47,50). An acute oral K + load enhanced ENaC cleavage and ENaC activity in rats and mice (18,38,52). A clear limitation of the present studies is the lack of consecutive plasma K + concentration measurements during nephrosis and the present tissue observations from day 8 after nephrosis could be too late to detect such changes in kidney tissue ENaC but it remains a possibility that the changes could be related to a primary increase in plasma K + in nephrotic syndrome.…”

Section: Discussionmentioning

confidence: 76%

Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Ydegaard

Svenningsen

Bistrup

et al. 2019

American Journal of Physiology-Renal Physiology

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The present study tested the hypotheses that nephrotic syndrome (NS) leads to renal K+ loss because of augmented epithelial Na+ channel (ENaC) activity followed by downregulation of renal K+ secretory pathways by suppressed aldosterone. The hypotheses were addressed by determining K+ balance and kidney abundance of K+ and Na+ transporter proteins in puromycin aminonucleoside (PAN)-induced rat nephrosis. The effects of amiloride and angiotensin II type 1 receptor and mineralocorticoid receptor (MR) antagonists were tested. Glucocorticoid-dependent MR activation was tested by suppression of endogenous glucocorticoid with dexamethasone. Urine and plasma samples were obtained from pediatric patients with NS in acute and remission phases. PAN-induced nephrotic rats had ENaC-dependent Na+ retention and displayed lower renal K+ excretion but elevated intestinal K+ secretion that resulted in less cumulated K+ in NS. Aldosterone was suppressed at day 8. The NS-associated changes in intestinal, but not renal, K+ handling responded to suppression of corticosterone, whereas angiotensin II type 1 receptor and MR blockers and amiloride had no effect on urine K+ excretion during NS. In PAN-induced nephrosis, kidney protein abundance of the renal outer medullary K+ channel and γ-ENaC were unchanged, whereas the Na+-Cl− cotransporter was suppressed and Na+-K+-ATPase increased. Pediatric patients with acute NS displayed suppressed urine Na+-to-K+ ratios compared with remission and elevated plasma K+ concentration, whereas fractional K+ excretion did not differ. Acute NS is associated with less cumulated K+ in a rat model, whereas patients with acute NS have elevated plasma K+ and normal renal fractional K+ excretion. In NS rats, K+ balance is not coupled to ENaC activity but results from opposite changes in renal and fecal K+ excretion with a contribution from corticosteroid MR-driven colonic secretion.

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Section: Discussionmentioning

confidence: 76%

Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Ydegaard

Svenningsen

Bistrup

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Besides the well-known functions of mTOR kinases, such as cell growth and metabolism (Hsu et al, 2011;Laplante & Sabatini, 2012), mTOR maintains renal tubular homeostasis by controlling transcellular transport processes (Grahammer et al, 2014), such as endocytosis and apical transport in proximal tubule cells and potassium secretion in the distal nephron (Grahammer et al, 2016(Grahammer et al, , 2017. A recent study has proposed that potassium itself may act through mTORC2 to activate the ENaCregulatory kinase SGK1, which in turn stimulates ENaC to enhance K + secretion (Sørensen et al, 2019). Our results extend the cellular paradigms of mTOR-regulated transport by demonstrating for the first time mTOR-dependent regulation of ion transport in non-epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Khakipoor

Giannaki

Theparambil

et al. 2019

Glia

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The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate and the main regulator of intracellular, extracellular, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1‐mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary mouse cortical astrocyte cultures, we investigated the effect of long‐term extracellular metabolic alkalosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H+ recording using the H+‐sensitive dye 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, and phosphoproteomic analysis. The results showed significant downregulation of NBCe1 activity following metabolic alkalosis without influencing protein abundance or surface expression of NBCe1. During alkalosis, the rate of intracellular H+ changes upon challenging NBCe1 was decreased in wild‐type astrocytes, but not in cortical astrocytes from NBCe1‐deficient mice. Alkalosis‐induced decrease of NBCe1 activity was rescued after activation of mTOR signaling. Moreover, mass spectrometry revealed constitutively phosphorylated S255‐257 and mutational analysis uncovered these residues being crucial for NBCe1 transport activity. Our results demonstrate a novel mTOR‐regulated mechanism by which NBCe1 functional expression is regulated. Such mechanism likely applies not only for NBCe1 in astrocytes, but in epithelial cells as well.

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“…GSEA showed decreased PI3K activity ( Figure 3B) and the anticipated change in PIP2, which activates ROMK (39,40), and decrease in WNK1 are upstream of mTOR regulation of potassium secretion (41) and are expected to enhance potassium secretion. The decrease in NEDD4L (LFC=-0.40, p=4.7e-34), which negatively regulates ENaC (42), would increase potassium secretion further.…”

Section: Diabetes Induces Gene Expression Changes That Promote Potassmentioning

confidence: 99%

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

Wilson

Kirita

et al. 2019

Preprint

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Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-typespecific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K + -ATPase, WNK1, mineralocorticoid receptor and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy. Significance StatementSingle nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.

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Potassium acts through mTOR to regulate its own secretion

Cited by 50 publications

References 56 publications

Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

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Potassium acts through mTOR to regulate its own secretion

Cited by 50 publications

References 56 publications

Nephrotic syndrome is associated with increased plasma K+concentration, intestinal K+losses, and attenuated urinary K+excretion: a study in rats and humans

Nephrotic syndrome is associated with increased plasma K+concentration, intestinal K+losses, and attenuated urinary K+excretion: a study in rats and humans

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

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Product

Resources

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Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans