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NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4+ Excretion, and Early Recovery from Metabolic Acidosis

Jeppe S. M. Olsen, Samuel Svendsen, Peder Berg, Vibeke S. Dam, Mads V. Sorensen, Vladimir V. Matchkov, Jens Leipziger and Ebbe Boedtkjer
JASN January 2021, ASN.2019060613; DOI: https://doi.org/10.1681/ASN.2019060613
Jeppe S. M. Olsen
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Samuel Svendsen
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Peder Berg
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Vibeke S. Dam
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Mads V. Sorensen
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Vladimir V. Matchkov
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Jens Leipziger
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
2Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark
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Ebbe Boedtkjer
1Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Significance Statement

Recovery from metabolic acidosis necessitates increased renal net acid excretion through urinary elimination of NH4+. Renal thick ascending limbs (TALs) contribute to a medullary shortcut, where NH4+ originating from proximal tubules is ultimately secreted in collecting ducts. NH4+ transfer across TALs requires a basolateral exit pathway for H+ to avoid intracellular accumulation. Experiments with knockout mice show that the Na+/HCO3− cotransporter NBCn1 mediates basolateral HCO3− uptake and increases NH4+ reabsorption in TAL, amplifies the corticomedullary NH4+ gradient, elevates the capacity for urinary NH4+ excretion, and accelerates recovery of arterial blood pH and [HCO3−] during metabolic acidosis. NBCn1 is crucial for acid-base handling in TALs, and for early renal compensation of systemic acid-base disturbances.

Abstract

Background The electroneutral Na+/HCO3− 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 NH4+ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH4+] was measured in renal biopsies, NH4+ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.

Results Basolateral Na+/HCO3− cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na+/HCO3− 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 NH4+ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH4+ gradient, reduced the capacity for urinary NH4+ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO3−] from their initial decline.

Conclusions During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO3− uptake and transepithelial NH4+ reabsorption in mTALs, renal medullary NH4+ accumulation, urinary NH4+ excretion, and early recovery of arterial blood pH and standard [HCO3−]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H+ released during NH4+ reabsorption across mTALs.

  • acidosis
  • cell & transport physiology
  • intracellular pH
  • ion transport
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (3)
Journal of the American Society of Nephrology
Vol. 32, Issue 3
March 2021
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NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4+ Excretion, and Early Recovery from Metabolic Acidosis
Jeppe S. M. Olsen, Samuel Svendsen, Peder Berg, Vibeke S. Dam, Mads V. Sorensen, Vladimir V. Matchkov, Jens Leipziger, Ebbe Boedtkjer
JASN Jan 2021, ASN.2019060613; DOI: 10.1681/ASN.2019060613

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NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4+ Excretion, and Early Recovery from Metabolic Acidosis
Jeppe S. M. Olsen, Samuel Svendsen, Peder Berg, Vibeke S. Dam, Mads V. Sorensen, Vladimir V. Matchkov, Jens Leipziger, Ebbe Boedtkjer
JASN Jan 2021, ASN.2019060613; DOI: 10.1681/ASN.2019060613
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  • ion transport

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