ArticleImmunity2021
APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.
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Article in Immunity, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
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53 citing papers in PubMed, 94 citations in OpenAlex.
- Update on APOL1 and chronic kidney diseases in children.Pediatric nephrology (Berlin, Germany) · 2026Review
- Coding, modifier, and regulatory effects shape circulating APOL1 levels.Human molecular genetics · 2026Article
- Nucleic acid sensing pathways in kidney disease development.Nature reviews. Nephrology · 2026Review
- Endothelial prolyl hydroxylase 3 mitigates maladaptive inflammation to promote post-ischemic kidney repair.Kidney international · 2026Article
- Proteomic risk score for early prediction of kidney disease progression in individuals with APOL1 high-risk genotypes.Nature medicine · 2026Article
- Hyperlipidemia in membranous nephropathy.Clinical kidney journal · 2026Review
- cGAS-STING pathway in innate immunity and its cell-specific role in kidney diseases.Frontiers in immunology · 2026Review
- APOL1 G1 and G2 risk alleles modulate severity of diet-induced obesity in a transgenic mouse model.bioRxiv : the preprint server for biology · 2025Article
- APOL1-mediated kidney disease: a narrative review of the lessons learnt from the past 15 years.BMC nephrology · 2025Review
- APOL1 kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney international · 2025Article
- APOL1 risk variants induce metabolic reprogramming of podocytes in patient-derived kidney organoids.Stem cell reports · 2025Article
- Hypertensive Nephrosclerosis: Pathological Changes and Overlap with Diabetic Nephropathy.Cureus · 2025Review
- Review
- G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway.bioRxiv : the preprint server for biology · 2025Article
- Apolipoprotein-L1 G1 variant contributes to hydrocephalus but not to atherosclerosis in apolipoprotein-E knock-out mice.Clinical science (London, England : 1979) · 2025Article
- The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene.Cell reports · 2025Article
- SGLT2 inhibitor empagliflozin ameliorates tubulointerstitial fibrosis in DKD by downregulating renal tubular PKM2.Cellular and molecular life sciences : CMLS · 2025Article
- Review
- Pathogenesis of HIV-associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environment interactions.American journal of physiology. Renal physiology · 2024Review
- Modeling lung endothelial dysfunction in sepsis-associated ARDS using a microphysiological system.Physiological reports · 2024Article
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Authors and funding
18 authors at 5 institutions in 2 countries.
Junnan WuRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Ziyuan MaRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Archana RamanRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Pazit BeckermanRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Poonam DhillonRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Dhanunjay MukhiRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Matthew PalmerDepartment of Pathology and Laboratory Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hua Chang ChenDivision of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
Cassiane Robinson CohenDivision of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Nephrology & Hypertension, Vanderbilt Precision Nephrology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
Thomas DunnPulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
John ReillyPulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nuala MeyerPulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Michael ShashatyPulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zoltan AranyCardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
György HaskóDepartment of Anesthesiology, Columbia University, New York, NY 10032, USA.
Krzysztof LaudanskiDepartment of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Adriana HungDivision of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Nephrology & Hypertension, Vanderbilt Precision Nephrology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
Katalin SusztakRenal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: ksusztak@pennmedicine.upenn.edu.
University of Pennsylvania · USTranslational Therapeutics (United States) · USVanderbilt University · USColumbia University · USShanghai Jiao Tong University · CN
Funding
Role of the Notch Pathway in Kidney InjuryR01DK076077 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI KATALIN SUSZTAK · 2007 to 2026
$8.0MEpigenetics of Chronic Kidney DiseaseR01DK087635 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI KATALIN SUSZTAK · 2009 to 2026
$7.0MAPOL1 associated kidney diseaseR01DK105821 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI SUSZTAK, KATALIN · 2016 to 2024
$4.6MTargeting Angiopoietin-2 in ARDSR01HL137006 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MEYER, NUALA JENNINGS · 2017 to 2021
$2.5MReconsidering the IL-1 axis in sepsis-associated ARDSR01HL137915 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MEYER, NUALA JENNINGS · 2017 to 2020
$2.1MThe role of cytosolic nucleotide sensors in inflammatory fibrosisR01DK132630 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI SUSZTAK, KATALIN · 2022 to 2025
$2.0MMentoring Patient-Oriented Research to Promote ARDS Precision MedicineK24HL155804 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MEYER, NUALA JENNINGS · 2021 to 2021
$124kCSRD VA I01 CX001897NHLBI NIH HHS K24 HL155804NHLBI NIH HHS R01 HL137006NHLBI NIH HHS R01 HL137915NIDDK NIH HHS R01 DK076077NIDDK NIH HHS R01 DK087635NIDDK NIH HHS R01 DK105821NIDDK NIH HHS R01 DK132630
Abstract
The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.
Indexed as
AnimalsApolipoprotein L1Black PeopleCOVID-19DNA, MitochondrialEndothelial CellsGenetic Predisposition to DiseaseHumansInflammationMembrane ProteinsMiceMice, KnockoutMitophagyNLR Family, Pyrin Domain-Containing 3 ProteinRisk FactorsSepsisAPOL1 protein, humanApolipoprotein L1DNA, MitochondrialMembrane ProteinsNLR Family, Pyrin Domain-Containing 3 ProteinNlrp3 protein, mouseSting1 protein, mouseSTING ProteinAPOL1COVID-19endothelial cellmitophagysepsis
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