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NRF2 regulates the glutamine transporter Slc38a3 (SNAT3) in kidney in response to metabolic acidosis

Lister, Adam and Bourgeois, Soline and Imenez Silva, Pedro H. and Rubio-Aliaga, Isabel and Marbet, Philippe and Walsh, Joanne and Shelton, Luke M. and Keller, Bettina and Verrey, Francois and Devuyst, Olivier and Giesbertz, Pieter and Daniel, Hannelore and Goldring, Christopher E. and Copple, Ian M. and Wagner, Carsten A. and Odermatt, Alex. (2018) NRF2 regulates the glutamine transporter Slc38a3 (SNAT3) in kidney in response to metabolic acidosis. Scientific reports, 8 (1). p. 5629.

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Abstract

Expression of the glutamine transporter SNAT3 increases in kidney during metabolic acidosis, suggesting a role during ammoniagenesis. Microarray analysis of Nrf2 knock-out (KO) mouse kidney identified Snat3 as the most significantly down-regulated transcript compared to wild-type (WT). We hypothesized that in the absence of NRF2 the kidney would be unable to induce SNAT3 under conditions of metabolic acidosis and therefore reduce the availability of glutamine for ammoniagenesis. Metabolic acidosis was induced for 7 days in WT and Nrf2 KO mice. Nrf2 KO mice failed to induce Snat3 mRNA and protein expression during metabolic acidosis. However, there were no differences in blood pH, bicarbonate, pCO; 2; , chloride and calcium or urinary pH, ammonium and phosphate levels. Normal induction of ammoniagenic enzymes was observed whereas several amino acid transporters showed differential regulation. Moreover, Nrf2 KO mice during acidosis showed increased expression of renal markers of oxidative stress and injury and NRF2 activity was increased during metabolic acidosis in WT kidney. We conclude that NRF2 is required to adapt the levels of SNAT3 in response to metabolic acidosis. In the absence of NRF2 and SNAT3, the kidney does not have any major acid handling defect; however, increased oxidative stress and renal injury may occur.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Research
e-ISSN:2045-2322
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:25 Jan 2019 08:06
Deposited On:25 Jan 2019 08:06

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