Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes encoding polycystins, presents with progressive development of kidney cysts and eventual end-stage kidney disease (ESKD) with limited treatment options. Previous work showed that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of CFTR-mediated fluid secretion, mTOR, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knock-in point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have slow progression to ESKD, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 months of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype than males. Metformin treatment reduced the ratio of total kidney weight to body weight relative to age- and sex-matched untreated controls at both 9 and 12 months and reduced cystic index in females at 9 months. Metformin also increased glomerular filtration rate (GFR), lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 vs. untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Comparative Efficacy of Pharmacological Treatments for Adults With Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

“…Metformin is a novel and attractive therapeutic candidate for ADPKD. Metformin inhibits the mTOR and CFTR pathways and activates AMPK, which has been associated with reduced renal cyst growth in an ADPKD mouse model ( Takiar et al, 2011 ; Carullo et al, 2021 ; Pastor-Soler et al, 2022 ). In the present analysis, metformin also showed a favorable trend, but it was not significant, possibly because of a small sample size.…”

Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats

“…Additionally, recent data from preclinical studies in various renal disease models have also pointed towards a putative protective effect of metformin on the kidney. [14][15][16][17][18][19] In a previous experimental study, we have shown that preventive metformin treatment was able to strongly attenuate the development of severe CKD. In this scenario we found that metformin preserved renal function, reduced renal inflammation and prevented excessive fibrosis.…”

Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation

“…However, in clinical trials they showed loss of efficacy in the progression of renal impairment ( Serra et al, 2010 ; Walz et al, 2010 ; Lin et al, 2019 ). Preclinical studies have demonstrated also the efficiency of metformin, an activator of AMPK, in ADPKD treatment ( Takiar et al, 2011 ; Chang et al, 2017 ; Pastor-Soler et al, 2022 ). Recently, metformin was tested also in randomized clinical trials in which it has been shown that it is safe but slightly reduces renal impairment ( Seliger et al, 2018 ; Perrone et al, 2021 ).…”