Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease
ADPKD is the most common genetic renal disease, leading to renal failure in the vast majority of affected individuals. Standard therapy consists of blood pressure control and salt restriction. Tolvaptan further delays renal failure but side effects prevent its widespread use. Novel therapeutic approaches are needed. Recent evidence has identified inflammation as an important driver of ADPKD. Here we show a strong inflammatory signature in transcriptomes of early ADPKD in the mouse. IL1ß and IL18, effectors of inflammasome activation, are among the top upregulated transcripts. Inflammasomes act as part of the innate immune response to danger signals, including crystals. Induction of calcium oxalate crystals through dietary intervention in Pkd1 mutant mice aggravated the cystic phenotype. Treatment of Pkd1 mutant mice with the inflammasome inhibitor MCC950 significantly ameliorated the ADPKD phenotype. Analogous results were obtained through genetic silencing of the essential inflammasome component Asc in ADPKD mice. Interference with inflammasome activation in the ADPKD animals resulted in better renal function and decreased IL18 excretion in the urine. These findings identify inflammasome inhibition as a promising concept for the treatment of ADPKD. Overall design: We performed a transcriptional screen in mice with a time dependent targeted deletion of Pkd1. Pkd1flox/flox.Pax8rtTA.Tet-O-Cre mice underwent tetracycline induced tubular deletion of Pkd1 during postnatal week 5 and 6. At 10 weeks, the kidneys were analyzed by RNAseq and the transcripts compared to kidneys from non-cystic Pkd1flox/flox.Tet-O-Cre control animals lacking Pax8rtTA.