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

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish (US)
Article number109213
JournalClinical Immunology
Volume248
DOIs
StatePublished - Mar 2023

Keywords

  • ACSL4
  • Ferroptosis
  • GPX4
  • Iron
  • Liproxstatin
  • Lupus nephritis
  • SLE

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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