期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 315, 期 1, 页码 F173-F185出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00407.2017
关键词
dRTA; intercalated cells; knockout mice; Ncoa7; V-ATPase
资金
- National Institutes of Health (NIH) [DK-042956, DK-097124, HD-040793, S10-OD-021577-01]
- Massachusetts General Hospital (MGH)
- Boston Area Diabetes and Endocrinology Research Center [DK-57521]
- MGH Center for the Study of Inflammatory Bowel Disease [DK-43351]
- Charles and Ann Sanders Research Scholar Award at MGH
- European Research Council [311394]
- European Research Council (ERC) [311394] Funding Source: European Research Council (ERC)
- MRC [MC_EX_MR/P502005/1] Funding Source: UKRI
We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been defined. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoa7 gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6v1b1 KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyper-bicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoa7 KO compared with wild-type mice, a phenotype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V-ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans.
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