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.
Highlights
The main function of metformin, a biguanide compound widely used for treatment of type 2 diabetes mellitus, is to lower the level of blood glucose[1,2] by inhibiting hepatic gluconeogenesis[3,4,5] and increase cellular glucose uptake[6,7]
The main results of the present study demonstrate that metformin treatment attenuates development of renal inflammation and tubular damage in the obstructed kidney in mice subjected to 3-day unilateral ureteral obstruction (3dUUO)
These results are consistent with a previous report where metformin treatment of ureteral obstruction (UUO) for 7 and 14 days attenuated the level of inflammatory markers TNFαand VCAM119
Summary
The main function of metformin, a biguanide compound widely used for treatment of type 2 diabetes mellitus, is to lower the level of blood glucose[1,2] by inhibiting hepatic gluconeogenesis[3,4,5] and increase cellular glucose uptake[6,7]. The expression of these mRNAs were increased in response to UUO, which was attenuated by metformin treatment (Fig. 1D,E). Metformin increased both the cytoprotective antioxidant NAD(P)H quinone oxidoreductase 1 (NQO1) mRNA expression and HO-1 protein levels in mice subjected to UUO, indicating that metformin upregulates the antioxidative response to 3dUUO (Fig. 4B,C).
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