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Abstract: SA-OR051

Inflammasome-Mediated Cell Death Plays a Key Role in APOL1 Risk Variant-Induced Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Raman, Archana, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ma, Ziyuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Laczko, Dorottya, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Seasock, Matthew J., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Group or Team Name

  • Susztak Lab

Apolipoprotein L1 (APOL1) coding variants, termed as G1 and G2 are associated with increased kidney disease risk. We developed a mouse model by conditional and inducible expression of reference (G0) or risk (G1 or G2) variants of APOL1. Mice with podocyte-specific G1 or G2 APOL1 expression develop albuminuria, glomerulosclerosis and renal failure recapitulating the human disease condition. However, molecular pathways leading to kidney disease development in this model remains poorly understood. We hypothesized that APOL1 risk alleles induced inflammasome-mediated pyroptotic cell death contributed to the phenotype development.


We generated cells with stable or inducible G2 APOL1 expression and used inhibitors of apoptosis, necrosis, and pyroptosis to determine pathways mediating cytotoxicity. To define the role of inflammasome-mediated cell death in vivo, we crossed G2 APOL1 transgenic mice (Nphs1rtTA-TRE APOL1) with caspase-1 (Casp1-/-) or NLRP3 (Nlrp3-/-) knockout mice and induced podocyte G2 APOL1 expression with a 21-day doxycycline diet. Histological changes were evaluated by PAS, fibrosis was quantified using Sirius red staining. Albuminuria was determined by ELISA. Inflammasome markers were quantified by immunoblotting.


We found that expression of inflammasome markers cleaved caspase-1, NLRP3, and IL-1B were higher in mice expressing risk variant APOL1. These results were recapitulated in cultured cells expressing risk variant APOL1, while pyroptosis inhibitors decreased inflammasome signaling and cytotoxicity. Nphs1rtTA-TRE APOL1/Casp1-/- mice showed a 90% reduction albuminuria, and a 73% decrease in renal fibrosis compared to Nphs1rtTA-TRE APOL1 mice. Nphs1rtTA-TRE APOL1/Nlrp3-/- mice showed an 80% reduction in albuminuria, and ~ 75% reduction in renal fibrosis, compared to G2 APOL1 littermates. Kidney histology examined by PAS and Sirius red staining showed significant improvement in kidney structure damage. Additionally, NLRP3 or caspase-1 knockout interchangeably decreased markers of inflammasome signaling and cell death.


Our data suggest that caspase-1 and NLRP3 inflammasome plays an important role in the development of G2 APOL1 induced kidney damage. Our results raise the possibility that inflammasome inhibition could be a potential therapeutic approach for APOL1-associated kidney disease.


  • NIDDK Support