In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 4 ( 2021-4), p. 852-865
Abstract:
Recovery from metabolic acidosis necessitates increased renal net acid excretion through urinary elimination of NH 4 + . Renal thick ascending limbs (TALs) contribute to a medullary shortcut, where NH 4 + originating from proximal tubules is ultimately secreted in collecting ducts. NH 4 + transfer across TALs requires a basolateral exit pathway for H + to avoid intracellular accumulation. Experiments with knockout mice show that the Na + /HCO 3 − cotransporter NBCn1 mediates basolateral HCO 3 − uptake and increases NH 4 + reabsorption in TAL, amplifies the corticomedullary NH 4 + gradient, elevates the capacity for urinary NH 4 + excretion, and accelerates recovery of arterial blood pH and [HCO 3 − ] during metabolic acidosis. NBCn1 is crucial for acid-base handling in TALs, and for early renal compensation of systemic acid-base disturbances. 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.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2019060613
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
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