Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice

Verouti, Sophia N.; Boscardin, Emilie; Hummler, Edith; Frateschi, Simona

doi:10.1016/j.coph.2014.12.012

Cited by 34 publications

(33 citation statements)

References 119 publications

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“…IL-17A −/− (but not WT) mice have significant blunting of the activation of distal sodium transporters. These are key transporters in the regulation of blood pressure as evidenced by the fact that thiazide diuretics, pharmacological inhibitors of NCC, are still one of the most effective drugs in the treatment of hypertension 23 . Moreover, many of the Mendelian forms of hypertension are due to mutations that influence the activity of NCC and/or the amiloride-sensitive ENaC.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

et al. 2016

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Angiotensin II (Ang II)-induced hypertension is associated with an increase in T cell production of interleukin 17A (IL-17A). Recently, we reported that IL-17A−/− mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 (NHE3) expression after 2 weeks of Ang II infusion compared to wild type (WT) mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, a time when the blood pressure reduction in IL-17A−/− mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased NHE3 expression through a serum and glucocorticoid regulated kinase 1 (SGK1) dependent pathway. In mouse distal convoluted tubule (mDCT15) cells, IL-17A increased NCC activity in an SGK1/Nedd4-2 dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of SGK1 at serine 78, and treatment with an SGK1 inhibitor blocked the effects of IL-17A on NHE3 and NCC. Interestingly, both HK-2 and mDCT15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

et al. 2016

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“…By the end of the 1990s, all members of the family were identified at the molecular level (17,41,42,45,84,97,98,150), providing the tools for detailed analysis of the renal expression of these cotransporters ( Fig. 1) to elucidate this family's role in Mendelian salt-losing nephropathies and to produce transgenic mouse models (25,52,142). Finally, in recent years, key regulatory phosphorylation sites were discovered in different SLC12 family members (24,46,80,95,106,109,113), allowing assessment of cotransporter activity using in vitro and in vivo systems.…”

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confidence: 99%

Physiological role of SLC12 family members in the kidney

Bazúa‐Valenti

Castañeda‐Bueno

Gamba

2016

American Journal of Physiology-Renal Physiology

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The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

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“…Aldosterone modulates ENaC activity by transcription‐dependent and ‐independent mechanisms (Thomas et al , ). Due to space constraints in this review, we refer to the extensive literature on ENaC regulation (Kellenberger and Schild, ; Rossier et al , ; Verouti et al , ).…”

Section: Amiloride‐sensitive Epithelial Sodium Channelmentioning

confidence: 99%

“…Next generation diuretics may block synergistically the Na + Cl − cotransporter (NCC) and ENaC, and possibly in addition the Cl − /HCO 3 − ‐exchanger pendrin in patients with fluid overloads such as congestive heart failure, nephrotic syndrome, diuretic resistance or generalized oedema. They may also block one or more pathways known to up‐regulate ENaC activity (reviewed in Rossier, ; Verouti et al , ).…”

Section: Amiloride‐sensitive Epithelial Sodium Channelmentioning

confidence: 99%

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19

Boscardin

Alijevic

Hummler

et al. 2016

British J Pharmacology

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122

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*These authors contributed equally.Acid-sensing ion channels (ASICs) and the epithelial Na + channel (ENaC) are both members of the ENaC/degenerin family of amiloride-sensitive Na + channels. ASICs act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. ENaC mediates Na + reabsorption across epithelia of the distal kidney and colon and of the airways. ENaC is a clinically used drug target in the context of hypertension and cystic fibrosis, while ASIC is an interesting potential target. Following a brief introduction, here we will review selected aspects of ASIC and ENaC function. We discuss the origin and nature of pH changes in the brain and the involvement of ASICs in synaptic signalling. We expose how in the peripheral nervous system, ASICs cover together with other ion channels a wide pH range as proton sensors. We introduce the mechanisms of aldosterone-dependent ENaC regulation and the evidence for an aldosterone-independent control of ENaC activity, such as regulation by dietary K + . We then provide an overview of the regulation of ENaC by proteases, a topic of increasing interest over the past few years. In spite of the profound differences in the physiological and pathological roles of ASICs and ENaC, these channels share many basic functional and structural properties. It is likely that further research will identify physiological contexts in which ASICs and ENaC have similar or overlapping roles. AbbreviationsAQP, aquaporin; ASDN, aldosterone-sensitive distal nephron; ASIC, acid-sensing ion channel; BASIC, bile acid-activated ion channel; BK, big calcium-activated K + channel; CA, carbonic anhydrase; CAP-1, -2, or-3, channel activating proteases; Ca v , voltage-gated Ca2 + channel; CCD, cortical collecting duct; CD, collecting duct; PHA-1, pseudohypoaldosteronism type 1; CFTR, cystic fibrosis transmembrane conductance regulator; CNT, connecting tubule; CF, cystic fibrosis; CLCN/Kb, voltage-sensitive chloride channel Kb; DCT, distal convoluted tubule; DRG, dorsal root ganglion; ENaC, amiloride-sensitive epithelial sodium channel; EPSP, excitatory post-synaptic potential; FaNaC, FMRFa-activated Na + channel; FMRFa, PheMet-Arg-Phe-amide; GMQ, 2-guanidine-4-methylquinazoline; GPI, glycosylphosphatidyl-inositol; HAI, hepatocyte growth factor activator inhibitor; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; I A , A-type current of rapid inactivating K + channels; iGluR, ionotropic glutamate receptor; I K , K + current; I Na , Na + current; I h , current produced by HCN channels; I max , maximal current amplitude; Kir, inward rectifier K + channel; K v , voltage-gated K + channel; MR, mineralocorticoid receptor; Na v , voltage-gated Na + channel; NBC, Na + , -HCO 3 -cotransporter; NCC, Na +-Cl À cotransporter; NHE, Na +-H + exchanger; OSR1/SPAK, Ste20-related protein kinases; P2X, purinergic receptor; PcTx1, Psalmotoxin 1; pH 50 , pH of half-maximal activation; pHe, extracellular pH; pH 50 Inh./Act., pH of h...

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Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice

Cited by 34 publications

References 119 publications

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

Physiological role of SLC12 family members in the kidney

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19

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Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice

Cited by 34 publications

References 119 publications

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II–Induced Hypertension

Physiological role of SLC12 family members in the kidney

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na+ channel (ENaC): IUPHAR Review 19

Contact Info

Product

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The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19