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

Sci Rep. 2018 Apr 4;8(1):5629. doi: 10.1038/s41598-018-24000-2.


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, pCO2, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis / physiopathology*
  • Amino Acid Transport Systems, Neutral / genetics
  • Amino Acid Transport Systems, Neutral / metabolism*
  • Amino Acids / analysis
  • Animals
  • Glutathione / metabolism
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / physiology*


  • Amino Acid Transport Systems, Neutral
  • Amino Acids
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • system N protein 1
  • Glutathione