The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

Abstract

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloridesensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na + and Cl -in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na + -driven Cl -/HCO 3 -exchanger (NDCBE/SLC4A8) and the Na + -independent Cl -/HCO 3 -exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na + reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

“…Since ENaC is not inhibited by thiazide, this mechanism was presumed to be independent of electrogenic Na + transport in principal cells. Subsequent studies have characterized the mechanism as one involving Na + -driven Cl − /2HCO 3 − exchanger (NDCBE) in β-intercalated cells; it was proposed that parallel operation of this exchanger and pendrin results in electroneutral NaCl transport (Leviel et al 2010). A recent follow-up study reported the physiological effects resulting from the loss of NDCBE.…”

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

“…Thus, both SPAK and OSR1 could be important vasopressin second messengers. Interestingly, using SPAK -/-mice, hibit significant net Na + or K + transport [9,10] . This does not mean that there is no functional ENaC or ROMK at the apical surface of PC in the CCD.…”

“…Regarding chloride transport, it has to be noted that such a secretion pathway has been partially described; it involves the basolateral transporter NKCC1 localized in the B-type intercalated B cells of the CCD [13] . Finally, significant net fluxes of Na + , Cl -and K + are measured in rat or mouse in vitro perfused CCD when animals are either submitted to a sodium-depleted diet or chronically treated with corticosteroids [9,10] . Therefore the CNT/CCD represents a functional "transport" reserve that can be recruited when Na + reabsorption (hypovolemia) and/or K + secretion (hyperkalemia) is needed [9,10] .…”

“…Finally, significant net fluxes of Na + , Cl -and K + are measured in rat or mouse in vitro perfused CCD when animals are either submitted to a sodium-depleted diet or chronically treated with corticosteroids [9,10] . Therefore the CNT/CCD represents a functional "transport" reserve that can be recruited when Na + reabsorption (hypovolemia) and/or K + secretion (hyperkalemia) is needed [9,10] . In humans, a gain-of-function mutation of ENaC induces a constitutively active Na + reabsorption in CNT and CD [14] .…”

“…Conversely, a loss-of-function mutation of the human ENaCα-subunit results in pseudo-hypo-aldosteronism 1 and is associated with urinary Na + wasting, low BP (at least in children) and hyperkalemia [16] . [10] , demonstrated a functional coupling between pendrin and a Na…”