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The AE4 transporter mediates kidney acid-base sensing.

ABSTRACT: The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na⁺-dependent Cl^-/HCO₃^- exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl^-/HCO₃^- exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.

SUBMITTER: Vitzthum H

PROVIDER: S-EPMC10220024 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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The AE4 transporter mediates kidney acid-base sensing.

Vitzthum H H Koch M M Eckermann L L Svendsen S L SL Berg P P Hübner C A CA Wagner C A CA Leipziger J J Meyer-Schwesinger C C Ehmke H H

Nature communications 20230526 1

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na+-dependent Cl-/HCO3- exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. ...[more]

PMID: 37236964

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Project description:Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in acid or base dietary intake. Because collecting ducts constitute the final site for regulating urine acid-base balance, we undertook to identify the gene network involved in acid-base transport and regulation in the mouse outer medullary collecting duct (OMCD). For this purpose, we combined kidney functional studies and quantitative analysis of gene expression in OMCDs, by transcriptome and candidate gene approaches, during metabolic acidosis. Furthermore, to better delineate the set of genes concerned with acid-base disturbance, the OMCD transcriptome of acidotic mice was both compared to that of normal mice and mice undergoing an adaptative response through potassium depletion. Metabolic acidosis, achieved through a NH4Cl-supplemented diet for 3 days, not only induced acid secretion, but also stimulated the aldosterone and vasopressin systems and triggered cell proliferation. Accordingly, metabolic acidosis increased the expression of genes involved in acid-base transport, sodium transport, water transport and cell proliferation. In particular, more than 25 transcripts encoding proteins involved in urine acidification (subunits of H-ATPase, kidney anion exchanger, chloride channel Clcka, carbonic anhydrase 2, aldolase) were co-regulated during acidosis. We propose that these trancripts cooperating to a same function and co-regulated during acidosis constitute a functional regulon. Keywords: SAGE; Kidney collecting duct; Mouse; Metabolic acidosis; V-ATPase Approximately 650 OMCDs were microdissected, as previously described from collagenase-treated kidneys of 6 mice fed the NH4Cl-supplemented diet for 3 days. 20960 tags were sequenced in the acidosis SAGE library. After withdrawing duplicate ditags and linker sequences, the 19146 tags remaining corresponded to 8847 different tags.This acidosis library is similar in size and diversity to the normal mouse OMCD libraries previously generated (GEO accession number : GSM23478). The tag abundance in the two library was compared and discussed.

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The AE4 transporter mediates kidney acid-base sensing.

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The AE4 transporter mediates kidney acid-base sensing.

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