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NBCn1 increases NH4+ reabsorption across thick ascending limbs, the capacity for urinary NH4+ excretion, and early recovery from metabolic acidosis

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NBCn1 increases NH4+ reabsorption across thick ascending limbs, the capacity for urinary NH4+ excretion, and early recovery from metabolic acidosis. / Olsen, Jeppe Steen; Svendsen, Samuel Levi Svinth C; Berg, Peder et al.

I: Journal of the American Society of Nephrology, Bind 32, Nr. 4, 04.2021, s. 852-865.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{851cf49354c4470faab67c485cf85e4d,
title = "NBCn1 increases NH4+ reabsorption across thick ascending limbs, the capacity for urinary NH4+ excretion, and early recovery from metabolic acidosis",
abstract = "BACKGROUND: The electroneutral Na +/HCO 3 - cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking. METHODS: Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH 4 + transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH 4 +] was measured in renal biopsies, NH 4 + excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice. RESULTS: Basolateral Na +/HCO 3 - cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na +/HCO 3 - cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH 4 + reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH 4 + gradient, reduced the capacity for urinary NH 4 + excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO 3 -] from their initial decline. CONCLUSIONS: During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO 3 - uptake and transepithelial NH 4 + reabsorption in mTALs, renal medullary NH 4 + accumulation, urinary NH 4 + excretion, and early recovery of arterial blood pH and standard [HCO 3 -]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H + released during NH 4 + reabsorption across mTALs. ",
keywords = "AMMONIUM, CELLS, COTRANSPORTER NBCN1, INTRACELLULAR PH, LOCALIZATION, NA+, PERFUSION, S0859, SLC4A7, TRANSPORT, acidosis, cell & transport physiology, intracellular pH, ion transport",
author = "Olsen, {Jeppe Steen} and Svendsen, {Samuel Levi Svinth C} and Peder Berg and Dam, {Vibeke Secher} and S{\o}rensen, {Mads Vaarby} and Vladimir Matchkov and Leipziger, {Jens Georg} and Ebbe Boedtkjer",
year = "2021",
month = apr,
doi = "10.1681/ASN.2019060613",
language = "English",
volume = "32",
pages = "852--865",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "The American Society of Nephrology",
number = "4",

}

RIS

TY - JOUR

T1 - NBCn1 increases NH4+ reabsorption across thick ascending limbs, the capacity for urinary NH4+ excretion, and early recovery from metabolic acidosis

AU - Olsen, Jeppe Steen

AU - Svendsen, Samuel Levi Svinth C

AU - Berg, Peder

AU - Dam, Vibeke Secher

AU - Sørensen, Mads Vaarby

AU - Matchkov, Vladimir

AU - Leipziger, Jens Georg

AU - Boedtkjer, Ebbe

PY - 2021/4

Y1 - 2021/4

N2 - BACKGROUND: The electroneutral Na +/HCO 3 - cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking. METHODS: Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH 4 + transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH 4 +] was measured in renal biopsies, NH 4 + excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice. RESULTS: Basolateral Na +/HCO 3 - cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na +/HCO 3 - cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH 4 + reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH 4 + gradient, reduced the capacity for urinary NH 4 + excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO 3 -] from their initial decline. CONCLUSIONS: During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO 3 - uptake and transepithelial NH 4 + reabsorption in mTALs, renal medullary NH 4 + accumulation, urinary NH 4 + excretion, and early recovery of arterial blood pH and standard [HCO 3 -]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H + released during NH 4 + reabsorption across mTALs.

AB - BACKGROUND: The electroneutral Na +/HCO 3 - cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking. METHODS: Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH 4 + transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH 4 +] was measured in renal biopsies, NH 4 + excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice. RESULTS: Basolateral Na +/HCO 3 - cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na +/HCO 3 - cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH 4 + reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH 4 + gradient, reduced the capacity for urinary NH 4 + excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO 3 -] from their initial decline. CONCLUSIONS: During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO 3 - uptake and transepithelial NH 4 + reabsorption in mTALs, renal medullary NH 4 + accumulation, urinary NH 4 + excretion, and early recovery of arterial blood pH and standard [HCO 3 -]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H + released during NH 4 + reabsorption across mTALs.

KW - AMMONIUM

KW - CELLS

KW - COTRANSPORTER NBCN1

KW - INTRACELLULAR PH

KW - LOCALIZATION

KW - NA+

KW - PERFUSION

KW - S0859

KW - SLC4A7

KW - TRANSPORT

KW - acidosis

KW - cell & transport physiology

KW - intracellular pH

KW - ion transport

U2 - 10.1681/ASN.2019060613

DO - 10.1681/ASN.2019060613

M3 - Journal article

C2 - 33414245

VL - 32

SP - 852

EP - 865

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 4

ER -