title: Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney.
abstract: 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 [11C]-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.
authors: Department of Clinical Medicine, Aarhus University, Denmark.
authors: Michael
authors: M
authors: Christensen
authors: Department of Clinical Medicine, Aarhus University, Denmark.|Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors: Jonas B
authors: JB
authors: Jensen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors: Steen
authors: S
authors: Jakobsen
authors: Department of Clinical Medicine, Aarhus University, Denmark.
authors: Niels
authors: N
authors: Jessen
authors: Department of Clinical Medicine, Aarhus University, Denmark.|Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors: Jørgen
authors: J
authors: Frøkiær
authors: 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.
authors: Bruce E
authors: BE
authors: Kemp
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Allison L
authors: AL
authors: Marciszyn
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Division of Nephrology and Hypertension, Department of Medicine and USC/UKRO Kidney Research Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors: Hui
authors: H
authors: Li
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Division of Nephrology and Hypertension, Department of Medicine and USC/UKRO Kidney Research Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors: Núria M
authors: NM
authors: Pastor-Soler
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Division of Nephrology and Hypertension, Department of Medicine and USC/UKRO Kidney Research Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors: Kenneth R
authors: KR
authors: Hallows
authors: Department of Clinical Medicine, Aarhus University, Denmark.
authors: Rikke
authors: R
authors: Nørregaard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050811:Octamer Transcription Factor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020011:Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000975:Antioxidants; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D050811:Octamer Transcription Factor-1; D000075102:Organic Cation Transporter 2; C494166:Pou2f1 protein, mouse; D020011:Protective Agents; C491012:Slc22a2 protein, mouse; D008687:Metformin; C554549:Prkab1 protein, mouse; D055372:AMP-Activated Protein Kinases