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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 48 citations

PubMed: 36566913 DOI: 10.1016/j.clim.2022.109213

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis.

Clin Immunol 248:109213

Authors: Abdel A Alli, Dhruv Desai, Ahmed Elshika, Marcus Conrad, Bettina Proneth, William Clapp, Carl Atkinson, Mark Segal, Louis A Searcy, Nancy D Denslow, Subhashini Bolisetty, Borna Mehrad, Laurence Morel, Yogesh Scindia

Affiliations

  • Department of Physiology and Aging, University of Florida, Gainesville, USA.
  • Department of Medicine, University of Florida, Gainesville, USA.
  • Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, USA.
  • Institute of Metabolism and Cell Death, Helmholtz Zentrum Munich, Germany.
  • Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, USA.
  • Department of Medicine, University of Alabama, Birmingham, USA.
  • Department of Medicine, University of Florida, Gainesville, USA; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, USA.

Abstract

Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments and an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme. Nephritic mice had an attenuated expression of SLC7A11, a cystine importer, an impaired glutathione synthesis pathway, and low expression of glutathione peroxidase 4, a ferroptosis inhibitor. Lipidomics of nephritic kidneys confirmed ferroptosis. Using nephrotoxic serum, we induced immune complex glomerulonephritis in congenic mice and demonstrate that impaired iron sequestration within the proximal tubules exacerbates ferroptosis. Lupus nephritis patient serum rendered human proximal tubular cells susceptibility to ferroptosis which was inhibited by Liproxstatin-2, a novel ferroptosis inhibitor. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in human and murine lupus nephritis.

MeSH

Cells, Serum, Epithelial Cells, Pathology, Ferroptosis, Lupus Nephritis, Kidney, Immune System Diseases, Nephritis, Glutathione

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