Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion

Bignon, Yohan; Pinelli, Laurent; Frachon, Nadia; Lahuna, Olivier; Figueres, Lucile; Houillier, Pascal; Lourdel, Stéphane; Teulon, Jacques; Paulais, Marc

doi:10.1016/j.kint.2019.09.028

Cited by 28 publications

(46 citation statements)

References 49 publications

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“…defects presented here 14 . The finding of a defective ammonia production in our patients despite intact urinary acidification is indeed consistent with a proximal tubular disturbance.…”

Section: Discussionmentioning

confidence: 68%

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Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Schlingmann

Renigunta

Hoorn

et al. 2021

JASN

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BackgroundThe transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.MethodsA candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.ResultsWe identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents.ConclusionsBiallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.

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“…defects presented here 14 . The finding of a defective ammonia production in our patients despite intact urinary acidification is indeed consistent with a proximal tubular disturbance.…”

Section: Discussionmentioning

confidence: 68%

“…KCNJ16 has also been shown to interact with KCNJ15 (Kir4.2) 5 , which is expressed on the basolateral membrane of proximal tubular cells. Notably, mice deleted for Kcnj15 display metabolic acidosis with a reduced threshold for bicarbonate and impaired ammoniagenesis 14 .…”

Section: Introductionmentioning

confidence: 99%

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Schlingmann

Renigunta

Hoorn

et al. 2021

JASN

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“…A recently developed Kcnj15 knockout mouse revealed that renal K ir 4.2 channels play a role in acid-base homeostasis distinct from K ir 4.1. The genetic deletion of K ir 4.2 caused metabolic acidosis with intracellular alkalization and membrane depolarization in PCT cells (4). Although specific channelopathies of renal K ir 4.2 have not been identified clinically thus far, KCNJ15 has been found to be downregulated in renal cell carcinoma and it has been suggested that it may have a role as a tumor suppressor and a potential therapeutic target (30).…”

Section: K Ir 42mentioning

confidence: 99%

Expression, localization, and functional properties of inwardly rectifying K⁺channels in the kidney

Manis

Hodges

Staruschenko

et al. 2020

American Journal of Physiology-Renal Physiology

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Inwardly rectifying K+ (Kir) channels are expressed in multiple organs and cell types and play critical roles in cellular function. Most notably, Kir channels are major determinants of the resting membrane potential and K+ homeostasis. The renal outer medullary K+ channel (Kir1.1) was the first renal Kir channel identified and cloned in the kidney over two decades ago. Since then, several additional members, including classical and ATP-regulated Kir family classes, have been identified to be expressed in the kidney and to contribute to renal ion transport. Although the ATP-regulated Kir channel class remains the most well known due to severe pathological phenotypes associated with their mutations, progress is being made in defining the properties, localization, and physiological functions of other renal Kir channels, including those localized to the basolateral epithelium. This review is primarily focused on the current knowledge of the expression and localization of renal Kir channels but will also briefly describe their proposed functions in the kidney.

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“…In other nephron segments, thyroid, and gastric parietal cells ( Lambrecht et al, 2005 ), Kir5.1 likely forms heteromeric channels with Kir4.2 and/or other Kir channels ( Figure 2A ). Kir4.2 is most highly expressed in renal proximal tubules, where it likely assembles with Kir5.1 to form basolateral K + channels ( Bignon et al, 2020 ; Figures 2A – C ). In addition to the tissues shown in Figure 2 , Kir4.1 and Kir5.1 are also expressed in the inner ear.…”

Section: Molecular and Biophysical Properties Of Kir41 And Kir51mentioning

confidence: 99%

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Forst

Warth

et al. 2022

Front. Physiol.

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In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

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Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion

Cited by 28 publications

References 49 publications

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Expression, localization, and functional properties of inwardly rectifying K⁺channels in the kidney

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

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Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion

Cited by 28 publications

References 49 publications

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Expression, localization, and functional properties of inwardly rectifying K+channels in the kidney

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

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Expression, localization, and functional properties of inwardly rectifying K⁺channels in the kidney