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

Autosomal dominant polycystic kidney disease (ADPKD) is associated with increased chemokines, cytokines and growth factors in the diseased kidney. We found that both isoforms of interleukin-1, IL-1a and IL-1b, were upregulated in ADPKD tissues. Here we employed a unique murine ADPKD model with selective deletion of pkd1 in the kidney (KPKD1) to study the role of IL-1 signaling in ADPKD progression. In KPKD mice, genetic deletion of the receptor for IL-1 (IL-1R KO) prolongs survival and attenuates cyst volume. Compared with IL-1R wild-type (WT) KPKD1 kidneys, IL-1R KO KPKD1 kidneys have upregulated TNF-a gene expression, with consequent elevations in markers for TNF-dependent regulated necrosis. We further observed that regulated necrosis is 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.