Steen Jakobsen

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney

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DOI

  • Michael Christensen
  • Jonas B Jensen
  • Steen Jakobsen
  • Niels Jessen
  • Jørgen Frøkiær
  • Bruce E Kemp, St. Vincent's Institute of Medical Research, University of Melbourne, Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy VIC 3065, Australia.
  • ,
  • Allison L Marciszyn, Renal-Electrolyte Division, Medicine Department, University of Pittsburgh School of Medicine, Pittsburgh, USA
  • ,
  • Hui Li, Renal-Electrolyte Division, Medicine Department, University of Pittsburgh School of Medicine, Pittsburgh, USA
  • ,
  • Núria M Pastor-Soler, Renal-Electrolyte Division, Medicine Department, University of Pittsburgh School of Medicine, Pittsburgh, USA
  • ,
  • Kenneth R Hallows, Renal-Electrolyte Division, Medicine Department, University of Pittsburgh School of Medicine, Pittsburgh, USA
  • ,
  • Rikke Nørregaard

The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs). To test whether the effects of metformin in the kidney are dependent on these transporters, we tested metformin treatment in OCT1/2(-/-) mice. Even though exposure of metformin in the kidney was severely decreased in OCT1/2(-/-) mice when evaluated with [(11)C]-Metformin and PET/MRI, we found that the protective effects of metformin were OCT1/2 independent when tested in this model. AMP-activated protein kinase (AMPK) has been suggested as a key mediator of the effects of metformin. When using an AMPK-β1 KO mouse model, the protective effects of metformin still occurred in the 3dUUO model. In conclusion, these results show that metformin has a beneficial effect in early stages of renal disease induced by 3dUUO. Furthermore, these effects appear to be independent of the expression of OCT1/2 and AMPK-β1, the most abundant AMPK-β isoform in the kidney.

Original languageEnglish
Article number35952
JournalScientific Reports
Volume6
Number of pages14
ISSN2045-2322
DOIs
Publication statusPublished - 26 Oct 2016

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