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

Journal Article (Journal Article)

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 IL-1, IL-1α and IL-1β, were upregulated in ADPKD tissues. Here, we used a unique murine ADPKD model with selective deletion of polycystin-1 (pkd1) in the kidney (KPKD1) to study the role of IL-1 signaling in ADPKD progression. In KPKD mice, genetic deletion of the IL-1 receptor [IL-1 receptor (IL-1R) knockout (KO)] prolongs survival and attenuates cyst volume. Compared with IL-1R wild-type KPKD1 kidneys, IL-1R KO KPKD1 kidneys have upregulated TNF-α 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.

Full Text

Duke Authors

Cited Authors

  • Yang, B; Fu, L; Privratsky, JR; Lu, X; Ren, J; Mei, C; Crowley, SD

Published Date

  • August 1, 2019

Published In

Volume / Issue

  • 317 / 2

Start / End Page

  • F221 - F228

PubMed ID

  • 31141402

Pubmed Central ID

  • PMC6732457

Electronic International Standard Serial Number (EISSN)

  • 1522-1466

Digital Object Identifier (DOI)

  • 10.1152/ajprenal.00104.2019


  • eng

Conference Location

  • United States