期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 317, 期 2, 页码 F221-F228出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00104.2019
关键词
autosomal dominant polycystic kidney disease; interleukin-1; necroptosis; tumor necrosis factor-alpha
资金
- National Institutes of Health Grants [DK-118019, HL-128355]
- United States Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development [BX-000893]
- American Heart Association Award [18TPA34170047]
- China Scholarship Council [201803170125]
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-1 alpha and IL-1 beta, 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-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据