Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury.
Authors Pedigo CE, Ducasa GM, Leclercq F, Sloan A, Mitrofanova A, Hashmi T, Molina-David
J, Ge M, Lassenius MI, Forsblom C, Lehto M, Groop PH, Kretzler M, Eddy S,
Martini S, Reich H, Wahl P, Ghiggeri G, Faul C, Burke GW, Kretz O, Huber TB,
Mendez AJ, Merscher S, Fornoni A
Submitted By Alessia Fornoni on 10/25/2016
Status Published
Journal The Journal of clinical investigation
Year 2016
Date Published
Volume : Pages 126 : 3336 - 50
PubMed Reference 27482889
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

Investigators with authorship
Alessia FornoniUniversity of Miami - Medical Campus
Matthias KretzlerUniversity of Michigan