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SIRT7 modulates the stability and activity of the renal K-Cl cotransporter KCC4 through deacetylation

ABSTRACT: SIRT7 is a NAD+-dependent deacetylase that controls important aspects of metabolism, cancer and bone formation. However, the molecular targets and functions of SIRT7 in the kidney are currently unknown. In silico analysis of kidney transcripts of the BXD murine genetic reference population revealed a positive correlation between Sirt7 and Slc12a7 mRNA expression, suggesting a link between the corresponding proteins that these transcripts encode, SIRT7 and the K-Cl cotransporter KCC4, respectively. Here, we found that protein levels and activity of heterologously expressed KCC4 are significantly modulated depending on its acetylation status in Xenopus laevis oocytes. Moreover, SIRT7 interacts with KCC4 in a NAD+-dependent manner and increases its stability and activity in HEK293 cells. Interestingly, metabolic acidosis increased SIRT7 expression in kidney, as occurs with KCC4. In contrast, total SIRT7-deficient mice presented lower KCC4 expression and an exacerbated metabolic acidosis than wild-type mice during an ammonium chloride challenge. Altogether, our data suggest that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.

SUBMITTER: Dr. Lilia, G Noriega

PROVIDER: S-SCDT-EMBOR-2020-50766V1 | biostudies-other |

REPOSITORIES: biostudies-other

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