دورية أكاديمية
أعرض في EDS

The key role of NLRP3 and STING in APOL1-associated podocytopathy.

التفاصيل البيبلوغرافية
العنوان: The key role of NLRP3 and STING in APOL1-associated podocytopathy.
المؤلفون: Wu J; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China., Raman A; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., 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 Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Kopp JB; Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA., Kuo JJ; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA., Pullen SS; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA., Boustany-Kari CM; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA., Linkermann A; Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany., Susztak K; Department of Medicine, Renal-Electrolyte and Hypertension Division, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2021 Oct 15; Vol. 131 (20).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Apolipoprotein L1/*genetics , Kidney Diseases/*etiology , Membrane Proteins/*physiology , NLR Family, Pyrin Domain-Containing 3 Protein/*physiology , Podocytes/*pathology, Animals ; Apolipoprotein L1/physiology ; Humans ; Mice
مستخلص: 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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معلومات مُعتمدة: R01 DK087635 United States DK NIDDK NIH HHS; R01 DK105821 United States DK NIDDK NIH HHS; R01 DK132630 United States DK NIDDK NIH HHS; Z01 DK043308 United States ImNIH Intramural NIH HHS
فهرسة مساهمة: Keywords: Cell Biology; Chronic kidney disease; Nephrology
المشرفين على المادة: 0 (Apolipoprotein L1)
0 (Membrane Proteins)
0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (STING1 protein, human)
0 (Sting1 protein, mouse)
تواريخ الأحداث: Date Created: 20211015 Date Completed: 20211203 Latest Revision: 20230614
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8516463
DOI: 10.1172/JCI136329
PMID: 34651582
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI136329