Metformin ameliorates the severity of experimental Alport syndrome

Abstract

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin also ameliorates tumor progression, inflammatory disease, and fibrosis. However, the ability of metformin to improve non-diabetic glomerular disease and chronic kidney disease (CKD) has not been explored. To investigate the effect of metformin on non-diabetic glomerular disease, we used a mouse model of Alport syndrome (Col4a5 G5X) which were treated with metformin or losartan, used as a control treatment. We also investigated the effect of metformin on adriamycin-induced glomerulosclerosis model. Pathological and biochemical analysis showed that metformin or losartan suppressed proteinuria, renal inflammation, fibrosis, and glomerular injury and extended the lifespan in Alport syndrome mice. Transcriptome analysis showed that metformin and losartan influenced molecular pathways-related to metabolism and inflammation. Metformin altered multiple genes including metabolic genes not affected by losartan. Metformin also suppressed proteinuria and glomerular injury in the adriamycin-induced glomerulosclerosis mouse model. Our results showed that metformin ameliorates the glomerular sclerosis and CKD phenotype in non-diabetic chronic glomerular diseases. Metformin may have therapeutic potential for not only diabetic nephropathy but also non-diabetic glomerular disease including Alport syndrome.

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

“…Several mouse models in Col4 α 3 , Col4 α 4 , and Col4 α 5 mutation have been known and characterized 7 – 11 , 14 . Col4 α 3 -/- or Col4 α 4 -/- mice are well used for studying treatments of Alport syndrome compared to Col4 α 5 -/Y mice 35 , 37 – 39 . Because, a survival ratio of Col4 α 5 -/Y mice was so diffusive ranged from 6 to 34 weeks 10 , in contrast, those of Col4 α 3 -/- or Col4 α 4 -/- mice were more uniform (from 13 to 26 weeks) 40 , 41 .…”

Creation of X-linked Alport Syndrome Rat Model withCol4a5Deficiency

“…6-10, 13 Col4α3 -/- or Col4α4 -/- mice are well used for studying treatments of Alport syndrome compared to Col4α5 -/Y mice. 28-31 Because, a survival ratio of Col4α5 -/Y mice was so diffusive ranged from 6 to 34 weeks, 9 in contrast, those of Col4α3 -/- or Col4α4 -/- mice were more uniform (from 13 to 26 weeks). 32, 33 In this study, Col4α5 mutant males died at 18 to 28 weeks (about 95 % from 20 to 26 weeks) of age.…”

Molecular and Cellular Mechanisms Underlying the Initiation and Progression of Alport Glomerular Pathology

“…Other targets include epigenetic modification by histone deacetylases ( 48 ), and matrix metalloproteinases including MMP 12 ( 49 ). Recently the diabetes drug metformin was shown to ameliorate the severity of Alport kidney disease in the XLAS mouse model ( 50 ). While metformin had no effect on extending lifespan in the 129 Sv ARAS model it did moderately increase lifespan in the Bl/6 XLAS model.…”

“…Preliminary work in humans using sodium-glucose cotransporter-2 inhibitors showed some promise in Alport patients and other forms of CKD, however larger numbers will be needed to see if the data is indeed significant ( 57 ). Importantly, none of these therapeutic approaches has been shown in animal models to provide any benefit beyond the standard of care (ACEi or ARBs) except for metformin, and for this only in the 129 Sv ARAS model ( 50 ).…”