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

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    Author
    Christensen, M; Jensen, JB; Jakobsen, S; Jessen, N; Frokiaer, J; Kemp, BE; Marciszyn, AL; Li, H; Pastor-Soler, NM; Hallows, KR; ...
    Date
    2016-10-26
    Source Title
    Scientific Reports
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Kemp, Bruce
    Affiliation
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Christensen, M., Jensen, J. B., Jakobsen, S., Jessen, N., Frokiaer, J., Kemp, B. E., Marciszyn, A. L., Li, H., Pastor-Soler, N. M., Hallows, K. R. & Norregaard, R. (2016). Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney. SCIENTIFIC REPORTS, 6 (1), https://doi.org/10.1038/srep35952.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257049
    DOI
    10.1038/srep35952
    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.

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