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The key role of NLRP3 and STING in APOL1-associated podocytopathy.
Wu, Junnan; Raman, Archana; Coffey, Nathan J; Sheng, Xin; Wahba, Joseph; Seasock, Matthew J; Ma, Ziyuan; Beckerman, Pazit; Laczkó, Dorottya; Palmer, Matthew B; Kopp, Jeffrey B; Kuo, Jay J; Pullen, Steven S; Boustany-Kari, Carine M; Linkermann, Andreas; Susztak, Katalin.
Afiliación
  • Wu J; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Raman A; Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • Coffey NJ; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Sheng X; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Wahba J; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Seasock MJ; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Ma Z; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Beckerman P; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Laczkó D; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Palmer MB; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Kopp JB; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Kuo JJ; Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Pullen SS; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
  • Boustany-Kari CM; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
  • Linkermann A; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
  • Susztak K; Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
J Clin Invest ; 131(20)2021 10 15.
Article en En | MEDLINE | ID: mdl-34651582
Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Podocitos / Proteína con Dominio Pirina 3 de la Familia NLR / Apolipoproteína L1 / Enfermedades Renales / Proteínas de la Membrana Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Podocitos / Proteína con Dominio Pirina 3 de la Familia NLR / Apolipoproteína L1 / Enfermedades Renales / Proteínas de la Membrana Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos