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.

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

“…sodium chloride cotransporter protein expression in female mice. 46 This sexual dimorphism may also apply to pendrin. This study finds consistent differences between SCTR WT and KO mice in both sexes and after adjustment for sex and age.…”

“…45 In addition to the SCTR, pendrin (SLC26A4), and CFTR, several other membrane proteins seem to have key roles in mediating/regulating urinary base excretion. The SLC4A9 (AE4) transporter, a suggested Na 1 -coupled HCO 3 2 transporter, was recently identified to play a critical role in regulation of pendrin function and to permit increases in renal base excretion 46 In addition, also the IRR is strongly expressed in the b-ICs and has an important role in regulating urine base excretion. 13 Thus, in chronic experiments (days), lack of the IRR was shown to abolish the increase of urine base excretion.…”

Novel functions of the anion exchanger AE4 (SLC4A9)

“…As such, single cell transcriptomics reported the highest AE4 expression in β-ICs, but also in murine [ 17 ] and human α-ICs [ 57 ], whereas principal cells showed no AE4 expression. Immunohistochemical approaches confirmed the presence of AE4 in the basolateral membrane of murine and human β-ICs [ 13 , 49 , 41 , 73 ]. Additionally, some pendrin-negative cells have been described to express AE4, which might represent α-ICs [ 32 , 26 , 41 ].…”

Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

“…22 However, the role of AE4 in salt homeostasis has been recently challenged. 23 The essential contribution of tight junctions in electrolyte homeostasis has not been detailed in this study. 24,25…”

“…22 However, the role of AE4 in salt homeostasis has been recently challenged. 23 The essential contribution of tight junctions in electrolyte homeostasis has not been detailed in this study. 24,25 ICs Sense and Trigger Inflammation Recent studies have unveiled the role of ICs in innate immune reaction and in renal inflammation.…”