Pendrin in the mouse kidney is primarily regulated by Cl⁻excretion but also by systemic metabolic acidosis

Abstract

The Cl(-)/anion exchanger pendrin (SLC26A4) is expressed on the apical side of renal non-type A intercalated cells. The abundance of pendrin is reduced during metabolic acidosis induced by oral NH(4)Cl loading. More recently, it has been shown that pendrin expression is increased during conditions associated with decreased urinary Cl(-) excretion and decreased upon Cl(-) loading. Hence, it is unclear if pendrin regulation during NH(4)Cl-induced acidosis is primarily due the Cl(-) load or acidosis. Therefore, we treated mice to increase urinary acidification, induce metabolic acidosis, or provide an oral Cl(-) load and examined the systemic acid-base status, urinary acidification, urinary Cl(-) excretion, and pendrin abundance in the kidney. NaCl or NH(4)Cl increased urinary Cl(-) excretion, whereas (NH(4))(2)SO(4), Na(2)SO(4), and acetazolamide treatments decreased urinary Cl(-) excretion. NH(4)Cl, (NH(4))(2)SO(4), and acetazolamide caused metabolic acidosis and stimulated urinary net acid excretion. Pendrin expression was reduced under NaCl, NH(4)Cl, and (NH(4))(2)SO(4) loading and increased with the other treatments. (NH(4))(2)SO(4) and acetazolamide treatments reduced the relative number of pendrin-expressing cells in the collecting duct. In a second series, animals were kept for 1 and 2 wk on a low-protein (20%) diet or a high-protein (50%) diet. The high-protein diet slightly increased urinary Cl(-) excretion and strongly stimulated net acid excretion but did not alter pendrin expression. Thus, pendrin expression is primarily correlated with urinary Cl(-) excretion but not blood Cl(-). However, metabolic acidosis caused by acetazolamide or (NH(4))(2)SO(4) loading prevented the increase or even reduced pendrin expression despite low urinary Cl(-) excretion, suggesting an independent regulation by acid-base status.

Regulated acid–base transport in the collecting duct

“…(57,67,203). During bicarbonate-loading increased pendrin abundance was observed, whereas potassium depletion caused reduced protein levels, an effect that may further enhance metabolic alkalosis during K + -restriction (57,203).…”

“…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). Studies in various cell lines provided evidence for direct regulatory domains in the promoter region sensitive to intracellular pH and possibly to aldosterone (1).…”

“…Studies in various cell lines provided evidence for direct regulatory domains in the promoter region sensitive to intracellular pH and possibly to aldosterone (1). A fourth and indirect means of regulation may be changes in the number of pendrin expressing non-type A intercalated cells as observed in states of chronic metabolic acidosis or altered distal chloride delivery associated with a changed relative abundance of pendrin positive cells (67,192,203).…”

Collecting Duct Intercalated Cell Function and Regulation

“…Several studies have confirmed that pendrin protein expression decreases with maneuvers that increase urinary Cl 2 excretion, while protocols that caused Cl 2 depletion, such as furosemide treatment, significantly increased pendrin levels. Later studies showed that metabolic acidosis induced by acetazolamide or ammonium sulfate administration reduced the levels of pendrin irrespective of low Cl 2 levels in urine (95). Aldosterone and angiotensin II also increase the levels of pendrin (96,97), thus linking this transport protein to the maintenance of adequate extracellular volume and potentially to the development of hypertension.…”

Proximal tubule Na+/H+ exchanger activity in adult NHE8−/−, NHE3−/−, and NHE3−/−/NHE8−/− mice

“…Briefly, we placed adult mice on 0.28 M ammonium chloride for 1 wk in 2% sucrose (to improve palatability) and in addition gavaged the mice daily for the last 4 days before the study with 0.033 mmol/g body wt NH 4Cl/g body wt (17,30). Controls were given equivalent amounts of NaCl in their drinking water or by gavage.…”