Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice
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). He...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Physiological Society
2018
|
| _version_ | 1797069500711960576 |
|---|---|
| author | Merkulova, M Păunescu, T Nair, A Wang, C Capen, D Oliver, P Breton, S Brown, D |
| author_facet | Merkulova, M Păunescu, T Nair, A Wang, C Capen, D Oliver, P Breton, S Brown, D |
| author_sort | Merkulova, M |
| collection | OXFORD |
| description | 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 hyperbicarbonatemia 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. |
| first_indexed | 2024-03-06T22:25:23Z |
| format | Journal article |
| id | oxford-uuid:567f4954-836f-41e5-81b9-8915227bb6ef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:25:23Z |
| publishDate | 2018 |
| publisher | American Physiological Society |
| record_format | dspace |
| spelling | oxford-uuid:567f4954-836f-41e5-81b9-8915227bb6ef2022-03-26T16:50:36ZTargeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in miceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:567f4954-836f-41e5-81b9-8915227bb6efEnglishSymplectic Elements at OxfordAmerican Physiological Society2018Merkulova, MPăunescu, TNair, AWang, CCapen, DOliver, PBreton, SBrown, DWe 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 hyperbicarbonatemia 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. |
| spellingShingle | Merkulova, M Păunescu, T Nair, A Wang, C Capen, D Oliver, P Breton, S Brown, D Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title | Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title_full | Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title_fullStr | Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title_full_unstemmed | Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title_short | Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| title_sort | targeted deletion of the ncoa7 gene results in incomplete distal renal tubular acidosis in mice |
| work_keys_str_mv | AT merkulovam targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT paunescut targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT naira targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT wangc targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT capend targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT oliverp targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT bretons targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice AT brownd targeteddeletionofthencoa7generesultsinincompletedistalrenaltubularacidosisinmice |