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Alli, A.A.* ; Desai, D.* ; Elshika, A.* ; Conrad, M. ; Proneth, B. ; Clapp, W.* ; Atkinson, C.* ; Segal, M.G.* ; Searcy, L.A.* ; Denslow, N.D.* ; Bolisetty, S.* ; Mehrad, B.* ; Morel, L.* ; Scindia, Y.*

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

Clin. Immunol. 248:109213 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Acsl4 ; Ferroptosis ; Gpx4 ; Iron ; Liproxstatin ; Lupus Nephritis ; Sle; Anti-dsdna Antibodies; Iron Homeostasis; Arachidonic-acid; Renal-disease; T-cells; Death; Pathogenesis; Chain; Mice; Erythematosus

ISSN (print) / ISBN 1521-6616

e-ISSN 1521-7035

Journal Clinical Immunology

Quellenangaben Volume: 248, Article Number: 109213

Publisher Elsevier

Publishing Place 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants NIH
Vifor Pharma