ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-PO462

Knockout of Caspase-1 Gene Restrains Polycystic Kidney Disease in Pkd1RC/RC Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Swenson-Fields, Katherine, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Ward, Christopher J., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Heimes Dillon, Anna L., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Vitek, Michael P., Resilio Therapeutics LLC, Durham, North Carolina, United States
  • Meisenheimer, James Derrick, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Fields, Timothy A., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Two stimuli shown to accelerate disease in PKD model mice are acute kidney injury and exposure to commensal microbes. A commonality of these two stimuli is that they both promote activation of the inflammasome, a multi-protein scaffold that assembles in a range of cell types as an innate immune response to either microbe-associated or cell damage-associated molecular motifs. Inflammasome assembly results in activation of the protease Caspase 1. Activated Caspase 1 promotes the cleavage and secretion of multiple protein substrates to create an inflammatory environment that can be pathological. We hypothesized that inflammasome activation promotes disease progression during the natural course of PKD.

Methods

To identify whether inflammasomes were activated during PKD progression, the expression of known inflammasome sensors/markers was assessed by qRT-PCR and western blotting of samples from the kidneys of human ADPKD patients, cystic jck and Pkd1RC/RC mice, and from non-cystic human and mouse kidneys. The jck mice were treated during an early stage of disease with adenine (2.5% in the chow), an agent known to activate inflammasomes, and the effects on PKD progression were examined at PN43. Caspase-1 (Casp1) was knocked out in the Pkd1RC/RC mice (Pkd1RC/RC:Casp1Δ/Δ). The effects on cystic kidney disease in Pkd1RC/RC and Pkd1RC/RC:Casp1Δ/Δ mice were assessed at 6 months of age.

Results

Elevated expression of inflammasome components was found in the jck and Pkd1RC/RC mice and human ADPKD kidneys (Nlrp3, Nlrp10, Mefv, Casp1, Il1b, NLRP3, CASP1 in jck; Nlrp1, Nlrp3, Aim2, Mefv, Casp1, Il1b in Pkd1RC/RC; NLRP1, NLRP3, NLP10, AIM2, CASP1, IL1B, NLRP3, IL1β in ADPKD). Adenine consumption promoted elevated 2K/TBW and cystic index in jck mice. Casp1 knockout lowered 2K/TBW (Pkd1RC/RC =2.2 ± 0.4, Pkd1RC/RC:Casp1Δ/Δ=1.8 ± 0.15, p=0.01; compared with WT=1.2 ± 0.13) and cystic index in Pkd1RC/RC mice.

Conclusion

These preclinical studies identify Caspase1 as a promoter of PKD progression and a potential therapeutic target for cystic kidney disease.

Funding

  • NIDDK Support