Interleukin-1 receptor activation aggravates autosomal dominant polycystic kidney disease by modulating regulated necrosis

摘要

In KPKD mice, genetic deletion of the IL-1 receptor IL-1 receptor (IL-1 R) knockout (KO) prolongs survival and attenuates cyst volume. Compared with IL-1R wild-type KPKD1 kidneys, IL-1R KO KPKD1 kidneys have upregulated TNF-alpha gene expression, with consequent elevations in markers for TNF-dependent regulated necrosis. We further observed that regulated necrosis was increased in ADPKD tissues from both humans and mice. To confirm that enhanced necroptosis is protective in ADPKD, we treated KPKD1 mice with an inhibitor of regulated necrosis (Nec-1). Regulated necrosis suppression augments kidney weights, suggesting that regulated necrosis is required to limit kidney growth in ADPKD. Thus, IL-1R activation drives ADPKD progression by paradoxically limiting regulated necrosis.