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The K + :Cl ‐ Cotransporter KCC4 is Activated by Deacetylation Induced by the Sirtuin7 (SIRT7)
Author(s) -
Mercado Adriana,
Melo Zesergio,
Tovar Armando,
Rajaram Renuga,
CruzRangel Silvia,
Ryu Dongreyol,
Torres Nimbe,
Staub Olivier,
Gamba Gerardo,
Noriega Lilia
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.666.24
Subject(s) - chemistry , metabolic acidosis , acidosis , cotransporter , acetylation , kidney , microbiology and biotechnology , biophysics , biochemistry , biology , endocrinology , sodium , gene , organic chemistry
KCC4 is expressed at the basolateral membrane of α‐intercalated cells where modulates pH balance. KCC4 expression in increased by metabolic acidosis and the absence of KCC4 causes renal tubular acidosis. The analysis of 41 recombinant inbred mouse strains kidney transcripts (GeneNetwork database) showed a positive correlation between KCC4 and SIRT7 mRNA expression, suggesting a link between these two proteins. Thus, in the present study we determined the intrarenal distribution of SIRT7 and analyzed its effect on KCC4 expression, acetylation and activity. In presence of nicotinamide (NAM) KCC4 is acetylated and its activity and protein levels are significantly reduced in Xenopus laevis oocytes and HEK‐293 cells. On the contrary, the presence of SIRT7 and its cofactor NAD + promote KCC4 deacetylation, increasing the protein levels and activity. Additionally, KCC4 and SIRT7 interact and the presence of NAD + enhances the process in HEK cells. Similar to KCC4, metabolic acidosis increased the protein levels of SIRT7 and its co‐localization with KCC4 at the basolateral membrane of α‐intercalated cells of mice‐collecting duct. In these cells, under metabolic acidosis, SIRT7 is translocated from the nucleus to the cytoplasm, where it can interact with KCC4. Finally, SIRT7 deficient mice have diminished KCC4 protein levels in the kidney and altered renal electrolyte excretion. Our data reveal that acetylation/deacetylation processes can regulate KCC4. SIRT7 co‐localize and interacts with KCC4 up‐regulating its activity by deacetylation. The positive effect of SIRT7 on KCC4 suggests a role for this sirtuin in acid‐base and renal electrolyte handling.