NaCl Restriction Upregulates Renal Slc26a4 Through Subcellular Redistribution

Abstract

Abstract-Slc26a4 (Pds, pendrin) is an anion transporter expressed in the apical region of type B and non-A, non-B intercalated cells of the distal nephron. It is upregulated by aldosterone analogues and is critical in the development of mineralocorticoid-induced hypertension. Thus, Slc26a4 expression and its role in blood pressure and fluid and electrolyte homeostasis was explored during NaCl restriction, a treatment model in which aldosterone is appropriately increased. Ultrastructural immunolocalization, balance studies, and cortical collecting ducts (CCDs) perfused in vitro were used. With moderate physiological NaCl restriction, Slc26a4 expression in the apical plasma membrane increased 2-to 3-fold in type B intercalated cells. Because Slc26a4 transports Cl Ϫ , we tested whether NaCl balance differs in Slc26a4 (ϩ/ϩ) (Ϫ/Ϫ) mice had evidence of relative vascular volume depletion because they had a higher arterial pH, hematocrit, and blood urea nitrogen than wild-type mice. With moderate NaCl restriction, blood pressure was similar in Slc26a4 (ϩ/ϩ) and Slc26a4 (Ϫ/Ϫ) mice. However, on a severely restricted intake of NaCl, Slc26a4 (Ϫ/Ϫ) mice were hypotensive relative to wild-type mice. We conclude that Slc26a4 is upregulated with NaCl restriction and is critical in the maintenance of acid-base balance and in the renal conservation of Cl Ϫ and water during NaCl restriction.

Pendrin Regulation in Mouse Kidney Primarily Is Chloride-Dependent

“…In contrast, ␣-ENaC expression was increased (155 Ϯ 11% in HCTZ group versus 100 Ϯ 5% in vehicle group; P Ͻ 0.001; Figure 3, A and C), ␥-ENaC expression showed a shift from the 85-to the 70-kD band (70 kD: 351 Ϯ 23% in HCTZ group versus 100 Ϯ 20% in vehicle group [P Ͻ 0.0001]; 85 kD: 53 Ϯ 4% in HCTZ group versus 100 Ϯ 7% in vehicle group [P Ͻ 0.0001]; Figure 3, A and D), and ␤-ENaC expression was decreased (47 Ϯ 5% in HCTZ group versus 100 Ϯ 6% in vehicle group; P Ͻ 0.0001; Figure 3, A and E), consistent with previous results from rat models with elevated plasma aldosterone levels (23,26). Because recent data indicate that subcellular redistribution of pendrin is an important mechanism of pendrin regulation (15,16,21), the possibility exists that total protein abundance as assessed by Western blot on renal membrane fractions may not represent the physiologically active pool of pendrin. Therefore, we next assessed whether HCTZ treatment induced a translocation of pendrin protein to the apical membrane while total protein abundance was decreased.…”

“…Cl Ϫ transport does not occur through principal cells but rather through the paracellular pathway or through the intercalated cells (11). In the B and non-A non-B type intercalated cells, pendrin, an apical anion exchanger (12)(13)(14), is believed to play a key role in BP regulation, most likely by controlling distal nephron chloride reabsorption (15,16). Pendrin is upregulated by the injection of deoxycorticosterone pivalate, a pharmacologic analogue of aldosterone (16).…”

Regulated acid–base transport in the collecting duct

“…Apparently, pendrin expression is sensitive to luminal chloride concentration but less to systemic chloride status. A role of pendrin in collecting duct chloride reabsorption is further supported by the findings that pendrin expression is regulated during chloride depletion (197,208), Pds KO mice are resistant to DOCA and NaCl induced hypertension (196), and angiotensin II stimulates chloride reabsorption in isolated CCDs from wildtype but not from pendrin deficient mice (132) Pendrin activity may be controlled on at least four different levels, namely mRNA and protein expression as well as subcellular localization. Enhanced luminal pendrin localization was observed in animals loaded with bicarbonate (203), given DOCA (196), or during chloride depletion (197), whereas several treatments altered total pendrin abundance in the kidney (57,67,139,192,203).…”

Two cases of eating disorder revealed by the breakout of acute kidney injury after angiotensin II receptor blocker administration

“…excretion conversely increases, leading to low urine pH (which is so called 'paradoxical aciduria'). As for urinary excretion of chloride, especially in a chloride-depletion state, transcellular reabsorption via the chloride-bicarbonate exchanger (known as pendrin, encoded by the SLC26A4 gene) at the apical membrane of beta-intercalated cells in connecting tubules and cortical collecting ducts is thought to play a quantitatively greater role [7,8]. In case 1, urinary electrolytes were measured at two points (shown in Fig.…”