Metformin’s action on diabetic nephropathy

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Despite a large panel of antidiabetic agents, it is assumed that between 20 and 40% of patients with diabetes ultimately develop diabetic nephropathy. Diabetic nephropathy is a microvascular complication of diabetes, others including diabetic retinopathy and diabetic neuropathy. Because metformin is excreted by the kidney, the reduction of metformin renal clearance is considered as an important risk factor of lactic acidosis. In consequence, it is recommended to review the dose of metformin if the serum creatinine exceeds 130 µmol/l (or estimated glomerular filtration rate is <45 ml/min/1.73 m²) and to stop metformin treatment if the creatinine levels rises above 150 µmol/l (or estimated glomerular filtration rate is below 30 ml/min/1.73 m²) [1]. But recently, some data accumulate suggesting that metformin could favour a protection against the deleterious consequences of hyperglycemia in kidney. Some of these data come from rodent models of diabetes as the Zucker diabetic fatty rats. In this model, Takiyama et al. demonstrated that metformin treatment (250 mg/kg/d) during 9 to 39 weeks ameliorates tubular injury associated with hyperglycemia while no protective effect was observed with insulin [62]. The authors showed that metformin specifically reduces HIF-1 expression (and their specific target genes) not only by reducing ATP synthesis but also by a drop of renal oxygen consumption in renal cells. Interestingly, the beneficial effect of metformin is preserved after knockdown of AMPKa subunit and can not be reproduced by AICAR (AMPK activator) or rapamycin (mTORC1 inhibitor) [62]. This suggested that, in this case, metformin acts independently of AMPK by decreasing renal oxygen consumption. Because chronic hypoxia and consequent increased HIF-1 expression are now considered as a key event during the initiation and progression of diabetic nephropathy and kidney fibrosis, the management of renal chronic hypoxia becomes a new therapeutic strategy for the prevention of diabetic nephropathy. It has been also demonstrated that metformin prevents gentamicin-induced acute renal failure, presumably by decreasing reactive oxygen species (ROS)-mediated lipid peroxidation [63], and decreases the TGFb-induced epithelial-to-mesenchymal transition (EMT), a key event in the development of the tubulointerstitial fibrosis during the diabetic nephropathy [64].

It is now well accepted that hyperglycemia increases ROS production in diabetic podocytes, contributing to the development of diabetic nephropathy. Until now, all the strategies used to reduce the ROS production in diabetic kidney have failed. Interestingly, Piwkowska et al. showed that metformin activates AMPK and decreases the NAD(P)H oxidase activity, ultimately leading to reduction of ROS production in cultured podocytes [65]. In consequence, control of ROS production by metformin could be a new optimal strategy for the management of diabetic nephropathy. Recently, the deleterious role of lipotoxicity in kidney has been recognized in Goto-Kakizaki [66] and OLETF rats [67], two rodent models of T2D. In this last one, diabetic nephropathy was correlated with the kidney triglycerides content and metformin reduces fat content by decreasing SREBP-1, FAS and ACC expression in kidney [67]. The reduction of renal lipotoxicity by metformin could thus be a new strategy for the prevention of diabetic nephropathy. Another intriguing effect of metformin is a reduction of cystic growth in the dominant polycystic kidney disease mice model [68]. This beneficial effect has been explained by AMPK activation by metformin and subsequent inhibition of both CFTR and mTOR pathways, demonstrating that the drug can modulate multiple molecular pathways in the kidney.

The reduction of kidney damage in animal models of T2D has to be confirmed in clinical studies. Taken together, a careful revision of clinical recommendations, especially the contra-indications of metformin use, may be required, in agreement with recent literature reviews suggesting that metformin treatment could probably be extended to all diabetic patients [69, 70]. Thus, because the risk of lactic acidosis is extremely low while the use of metformin results in cardiovascular, renal and survival benefits, the use of metformin should be revised accordingly to clear glomerular filtration rate cut-off or adaptation of metformin dose by determination of its plasma levels [71].