mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

Gleason, Catherine E.; Frindt, Gustavo; Cheng, Chih Jen; Ng, Michael; Kidwai, Atif; Rashmi, Priyanka; Läng, Florian; Baum, Michel; Palmer, Lawrence G.; Pearce, David

doi:10.1172/jci73935

Cited by 70 publications

(74 citation statements)

References 49 publications

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“…We first performed patch-clamp experiments in native CCD treated with AZD8055, a potent and specific inhibitor of mTOR in both of its major complexes, mTORC1 and mTORC2. As shown in Figure 5A and Supplemental Table 1, AZD8055 suppressed current, as previously described (8), and abolished the difference in amiloride-sensitive current seen in 1 versus 5 mM K + . Similarly, in mpkCCD cells, AZD8055 blocked the ENaC-stimulatory effect of increasing [K + ] from 1 to 5 mM ( Figure 5B), in parallel with blocking SGK1 S422 phosphorylation ( Figure 5C).…”

Section: Resultssupporting

confidence: 81%

Potassium acts through mTOR to regulate its own secretion

Sørensen¹,

Saha²,

Jensen³

et al. 2019

JCI Insight

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Section: Resultssupporting

confidence: 81%

Potassium acts through mTOR to regulate its own secretion

Sørensen¹,

Saha²,

Jensen³

et al. 2019

JCI Insight

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“…mTORC1, which is a complex of mTOR, regulatory-associated protein of mTOR (Raptor) and several other proteins, regulates cell growth and proliferation and inhibits autophagy by stimulating anabolic processes. mTORC2, which is a complex of mTOR, rapamycin- insensitive companion of mTOR (Rictor) and several other proteins, is thought to regulate potassium and sodium levels in the kidney 48,49 . mTORC1 is considered a nutrient sensor because it can be activated by growth factors, nutrients such as amino acids and glucose, and oxidative stress, triggering pathways that lead to protein synthesis, nucleotide synthesis, lipid synthesis and mitochondrial biogenesis by activating the transcriptional repressor yin and yang 1 (YY1) 46,50 .…”

Section: Nutrient-sensing Pathways In the Kidneymentioning

confidence: 99%

Mitochondrial energetics in the kidney

2017

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The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

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“…Similar patch-clamp and calcium measurements in nephron segments are widely used on non-cystic kidneys in many laboratories [41][42][43] . Depending ion channels type, different modifications of patch-clamp method can be used (whole cell, inside-out, outside-out); for instance, ENaC and ROMK (renal outer medullary potassium channel) activity can be assessed by whole-cell configuration 44,45 . The proposed Fura-2 AM calcium imaging in wide-field epifluorescence with monochromator can be also performed with any other similar modification of calcium imaging such as analysis with confocal or two-photon microscopy with other calcium dyes.…”

Section: Discussionmentioning

confidence: 99%

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

Pavlov

Ilatovskaya

Palygin

et al. 2015

JoVE

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Cyst initiation and expansion during polycystic kidney disease is a complex process characterized by abnormalities in tubular cell proliferation, luminal fluid accumulation and extracellular matrix formation. Activity of ion channels and intracellular calcium signaling are key physiologic parameters which determine functions of tubular epithelium. We developed a method suitable for real-time observation of ion channels activity with patch-clamp technique and registration of intracellular Ca 2+ level in epithelial monolayers freshly isolated from renal cysts. PCK rats, a genetic model of autosomal recessive polycystic kidney disease (ARPKD), were used here for ex vivo analysis of ion channels and calcium flux. Described here is a detailed step-by-step procedure designed to isolate cystic monolayers and non-dilated tubules from PCK or normal Sprague Dawley (SD) rats, and monitor single channel activity and intracellular Ca 2+ dynamics. This method does not require enzymatic processing and allows analysis in a native setting of freshly isolated epithelial monolayer. Moreover, this technique is very sensitive to intracellular calcium changes and generates high resolution images for precise measurements. Finally, isolated cystic epithelium can be further used for staining with antibodies or dyes, preparation of primary cultures and purification for various biochemical assays. Video LinkThe video component of this article can be found at

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mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

Cited by 70 publications

References 49 publications

Potassium acts through mTOR to regulate its own secretion

Potassium acts through mTOR to regulate its own secretion

Mitochondrial energetics in the kidney

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

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