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.
Autosomal Dominant Polycystic Kidney Disease: New Treatment Options and How to Test Their Efficacy