As shown by various lines of evidence, AMPK activation is important for the beneficial effect of metformin on type 2 diabetes treatment 12, 13, 14.
AMPK is a metabolic sensor and has several beneficial effects on intracellular homeostasis, such as regulating glycolysis and lipid metabolism 11. This energetic stress increases intracellular AMP level, leading to AMP-activated protein kinase (AMPK) activation 10. Metformin, widely used for treatment of type 2 diabetes 8, inhibits mitochondrial respiratory chain complex 1 and transiently decreases mitochondrial energy production 9. Patients with Alport syndrome present with chronic glomerular dysfunction, renal inflammation, and fibrosis which are the hallmarks of CKD that progress to ESKD 7. Alport syndrome is a hereditary glomerular disease caused by mutation in the COL4A3, A4, or A5 gene encoding type IV collagen α3–5 (α3–5(IV)) chains, which are components of the glomerular basement membrane 5, 6. There are many causes of CKD, including hypertension, diabetes, and genetic mutation regardless of the cause, CKD commonly manifests proteinuria, renal inflammation, and fibrosis 1, 2, 3, 4. Metformin may have therapeutic potential for not only diabetic nephropathy but also non-diabetic glomerular disease including Alport syndrome.Ĭhronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is one of the major global health problems with high incidence, poor prognosis, and high medical cost. Our results showed that metformin ameliorates the glomerular sclerosis and CKD phenotype in non-diabetic chronic glomerular diseases. Metformin also suppressed proteinuria and glomerular injury in the adriamycin-induced glomerulosclerosis mouse model. Metformin altered multiple genes including metabolic genes not affected by losartan. Transcriptome analysis showed that metformin and losartan influenced molecular pathways-related to metabolism and inflammation. 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. We also investigated the effect of metformin on adriamycin-induced glomerulosclerosis model. 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. However, the ability of metformin to improve non-diabetic glomerular disease and chronic kidney disease (CKD) has not been explored. 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.
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