The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

Abstract

Background: The Slc4 family of bicarbonate transporters consists of several members, many of which are highly expressed in the kidney and play an important role in acid-base homeostasis. Among them are Ae1 (Slc4a1) and Ae2 (Slc4a2). Another member, Ae3 (Slc4a3), is suggested to be expressed in the kidney, however, its localization and impact on renal function is still unknown. Ae3 has also been implicated in the central control of breathing. Aims: Here, we analyzed the expression of Ae3 transcripts in isolated nephron segments and investigated systemic and renal acid-base homeostasis and renal electrolyte handling in the absence of Ae3, using a knock out mouse model. Methods: qPCR was used to localize Ae3 transcripts in the murine nephron, metabolic studies and whole body plethysmography to assess the role of Ae3 in renal functions. Results: Two Ae3 transcripts, the brain variant bAe3 and the cardiac variant cAe3, are expressed at low levels in the murine kidney. Although differentially distributed, they localize mostly to the distal nephron and renal collecting duct system. At baseline and after an acid challenge, mice deficient for Ae3 did not show major disturbances in renal acid-base excretion. Respiratory responses in whole body plethysmography to acid loading and CO2 and O2 challenges were normal. No major differences in renal electrolyte handling were discovered except for small changes in magnesium, potassium and sodium excretion after 7 days of acid loading. We therefore challenged mice with diets with high and low magnesium diets and found no differences in renal magnesium excretion but elevated expression of the Trpm6 magnesium channel in Ae3 KO mice. In conclusion, Ae3 is expressed in murine kidney at very low levels. Conclusions: Ae3 plays no role in systemic acid-base homeostasis but may modify renal magnesium handling inducing a higher expression of Trpm6.

Overlapping expression of anion exchangers in the cochlea of a non-human primate suggests functional compensation

“…The antibodies against SLC26A4, SLC26A6, SLC26A7, SLC4A2 and SLC4A3 used in this study exhibited immunoreactivity in the renal tubules or the collecting ducts and no immunoreactivity in the glomeruli, consistent with the previous reports in humans (Fig. 7) (Castillo et al, 2000;Kampik et al, 2014;Kim et al, 2002;Kujala et al, 2005;Soleimani, 2013;Xu et al, 2011).…”

“…Among anion exchangers, expression of the SLC26 and SLC4A families has been widely observed in these three organs among species, but their expression profiles and functions differ greatly among species. SLC4A2 (Castillo et al, 2000), SLC4A3 (Kampik et al, 2014), SLC26A1 (Karniski et al, 1998), SLC26A4 (Royaux et al, 2001), SLC26A6, SLC26A7 and SLC26A11 (Vincourt et al, 2003) are expressed in the mouse kidney. Although mutations in SLC26A4 gene cause Pendred syndrome, patients with this mutation do not suffer renal dysfunction in spite of the abundant expression of the PENDRIN protein in the proximal tubule and cortical collecting duct cells of the kidney.…”

Population Structure, and Selection Signatures Underlying High-Altitude Adaptation Inferred From Genome-Wide Copy Number Variations in Chinese Indigenous Cattle

“…SLC4A3 encodes a plasma membrane Cl -/HCO 3 exchanger AE3, which belongs to the anion exchanger Solute Carrier Family 4 (SLC4) (Alper et al, 2002;Thorsen et al, 2017). The SLC4A3 knockout mice exhibit normal respiratory response to changes in ambients O 2 or CO 2 but resistance to cardiomyocyte hypertrophy compared to wildtype littermates (Kampik et al, 2014;Sowah et al, 2014). The loss of heterozygosity at SLC4A3 gene locus happened only in high-altitude cattle in current study, which may benefit in resisting the right-ventricle hypertrophy and maitaining healthy heart function under hypoxia.…”

RNA SEQ Analysis Indicates that the AE3 Cl−/HCO3 − Exchanger Contributes to Active Transport-Mediated CO2 Disposal in Heart

“…The changes in angiogenesis genes that play direct roles in vascular tissues, while modest, were unambiguously consistent with a reduction in angiogenesis in AE3-null hearts, which initially seemed inconsistent with the apparent hypoxia response. However, the hypoxia response is not due to systemic hypoxia, as global loss of AE3 does not affect respiratory function, systemic acid-base homeostasis, or blood gasses (O 2 , CO 2 ) 127 . Also, the level of blood lactate, which is utilized as an energy source by cardiac myocytes, is slightly reduced 127 rather than increased as in systemic hypoxia.…”

“…However, the hypoxia response is not due to systemic hypoxia, as global loss of AE3 does not affect respiratory function, systemic acid-base homeostasis, or blood gasses (O 2 , CO 2 ) 127 . Also, the level of blood lactate, which is utilized as an energy source by cardiac myocytes, is slightly reduced 127 rather than increased as in systemic hypoxia. Furthermore, systemic hypoxia should increase, not decrease, angiogenesis.…”