Metformin ameliorates the severity of experimental Alport syndrome

Kohei Omachi,Hirofumi Kai,Kosuke Koyama,Keisuke Teramoto,Hirofumi Nohara,Shota Kaseda,Haruka Kojima,Tsuyoshi Shuto,Jeffrey H Miner,Naomi Nakagata,Jian-Dong Li,Tsubasa Yokota,Shogo Misumi,Toru Takeo,Jun Kuwazuru,Sumio Ohtsuki,Misato Kamura,Mary Ann Suico

doi:10.1038/s41598-021-86109-1

Kohei Omachi, Hirofumi Kai + Show 16 more

Open Access

https://doi.org/10.1038/s41598-021-86109-1

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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.

Highlights

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin ameliorates tumor progression, inflammatory disease, and fibrosis
Previous studies showed that metformin ameliorates renal inflammation and fibrosis in experimental mouse models, including unilateral ureteral obstruction (UUO)[14], cisplatin-induced tubular injury[17], and ischemia–reperfusion (I/R) injury[18,19], all of which are classified as acute kidney injury
Because metformin is an anti-diabetic agent with reported increased risk of lactic acidosis[24], we evaluated its effect on body weight, water intake, urine volume, blood glucose and serum lactate levels in Col4a5 G5X Alport syndrome mice

Summary

Introduction

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin ameliorates tumor progression, inflammatory disease, and fibrosis. 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 investigated the effect of metformin on chronic glomerular disease using a mouse model of Alport syndrome (Col4a5 G5X mutant mice)[20]. This Alport syndrome mouse model spontaneously shows progressive glomerular disease and CKD phenotypes, including renal inflammation and fibrosis. Using this model, we demonstrate that metformin has a protective effect on non-diabetic and chronic glomerular disease

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