Local TNF mediates free cholesterol–dependent podocyte injury
Some patients with diabetes develop diabetic kidney disease (DKD), which can progress to a loss of renal function. High levels of TNF are predictive of disease and organ damage; however, it is not clear how elevated TNF promotes injury. In this episode, Alessia Fornoni reveals that TNF promotes free cholesterol–dependent podocyte apoptosis via an NFATc1/ ABCA1-dependent mechanism. The results of this study indicate that agents targeting cholesterol efflux should be further explored for treating proteinuric kidney diseases.
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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-
Authors
Christopher E. Pedigo, Gloria Michelle Ducasa, Farah Leclercq, Alexis Sloan, Alla Mitrofanova, Tahreem Hashmi, Judith Molina-David, Mengyuan Ge, Mariann I. Lassenius, Carol Forsblom, Markku Lehto, Per-Henrik Groop, Matthias Kretzler, Sean Eddy, Sebastian Martini, Heather Reich, Patricia Wahl, GianMarco Ghiggeri, Christian Faul, George W. Burke III, Oliver Kretz, Tobias B. Huber, Armando J. Mendez, Sandra Merscher, Alessia Fornoni
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)