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.

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

“…Numerous in vitro and in vivo studies have indicated that metformin attenuates renal fibrogenesis, mainly by activating activity biomarkers of AMP‐activated protein kinase and target of rapamycin, thus exerting an antiapoptotic effect on podocytes in a high‐glucose environment and reducing the loss of podocytes in DM nephropathy . Diabetic rats, when treated with 150, 300, or 500 mg/kg of metformin for 8 weeks, had significant dose‐dependent reductions in urinary albumin, nephrin concentration, 8‐hydroxydeoxyguanosine level, glomerular basement membrane thickness, and foot process fusion rate compared with the control type 2 model rats …”

“…8,[22][23][24] Diabetic rats, when treated with 150, 300, or 500 mg/kg of metformin for 8 weeks, had significant dose-dependent reductions in urinary albumin, nephrin concentration, 8-hydroxydeoxyguanosine level, glomerular basement membrane thickness, and foot process fusion rate compared with the control type 2 model rats. 25,26 The potential renoprotective effect of metformin has been challenged. Hsu et al 10 reported that continual use of metformin was associated with a decline in the estimated glomerular filtration rate in patients with type 2 DM and moderate CKD.…”

Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein‐2

“…The renal medulla is especially sensitive to hypoxia due to low blood perfusion and high basal levels of QO 2. The renoprotective effects of metformin have been reported in several animal studies, including unilateral ureteral obstruction and gentamicin‐induced nephropathy as well as in DKD . Metformin is a drug with pleotropic effects and has been suggested to protect against DKD through AMP‐activated protein kinase/mammalian target of rapamycin modulation, attenuation of hypoxia‐inducible factor 1‐alpha accumulation, and through modulation of oxidative stress‐related gene expression …”

Renoprotective Effects of Metformin

“…These abnormalities were improved by metformin, providing a protective effect on glomerular podocytes at a dose of 300 mg metformin/kg/day for 8 weeks and 350 mg metformin/kg/day for 17 weeks [59]. In mice, independent of the expression of OCT1/2 and AMPK-β1, metformin (500 mg/kg/day) has a beneficial effect in early stages of renal disease induced by unilateral ureteral obstruction [59].…”

“…These abnormalities were improved by metformin, providing a protective effect on glomerular podocytes at a dose of 300 mg metformin/kg/day for 8 weeks and 350 mg metformin/kg/day for 17 weeks [59]. In mice, independent of the expression of OCT1/2 and AMPK-β1, metformin (500 mg/kg/day) has a beneficial effect in early stages of renal disease induced by unilateral ureteral obstruction [59]. Pre-treatment with metformin at a dose of 25–100 mg/kg for 7 days shows protective effects in an ischaemia-reperfusion model induced in rats as indicated by improved kidney function, less development of fibrosis and structural alterations [60].…”