title: Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury.
abstract: High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pedigo
authors.forename: Gloria Michelle
authors.initials: GM
authors.lastname: Ducasa
authors.forename: Farah
authors.initials: F
authors.lastname: Leclercq
authors.forename: Alexis
authors.initials: A
authors.lastname: Sloan
authors.forename: Alla
authors.initials: A
authors.lastname: Mitrofanova
authors.forename: Tahreem
authors.initials: T
authors.lastname: Hashmi
authors.forename: Judith
authors.initials: J
authors.lastname: Molina-David
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Ge
authors.forename: Mariann I
authors.initials: MI
authors.lastname: Lassenius
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Sean
authors.initials: S
authors.lastname: Eddy
authors.forename: Sebastian
authors.initials: S
authors.lastname: Martini
authors.forename: Heather
authors.initials: H
authors.lastname: Reich
authors.forename: Patricia
authors.initials: P
authors.lastname: Wahl
authors.forename: GianMarco
authors.initials: G
authors.lastname: Ghiggeri
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Mendez
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000502:physiology; D000293:Adolescent; D000419:Albuminuria / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000737:chemistry*; D003505:Cyclodextrins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000097:blood*; D005260:Female; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood*; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000502:physiology*; D009404:Nephrotic Syndrome / Q000097:blood*; D050199:Podocytes / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D002785:Sterol O-Acyltransferase / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D003505:Cyclodextrins; D050778:NFATC Transcription Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D002785:Sterol O-Acyltransferase; D014409:Tumor Necrosis Factor-alpha; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; C493492:sterol O-acyltransferase 1