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

Abstract While the deposition of immune complexes in the glomeruli is thought to initiate lupus nephritis, the extent of tubular damage better predicts progression to end stage kidney disease than the glomerular injury. However, the mechanisms underlying tubular injury in lupus nephritis are incompletely understood. Iron accumulates in tubular epithelial cells of lupus nephritis patients and mice. Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Here we identify intra-renal ferroptosis as a novel pathological feature in human and murine lupus nephritis of different etiologies. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments. Nephritic kidneys presented with an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme, an impaired glutathione synthesis pathway, and attenuated expression of glutathione peroxidase 4, a glutathione-dependent ferroptosis inhibitor. Semi targeted lipidomics of murine nephritic kidneys revealed increased esterification of the sn-2 chain of phosphatidylethanolamine with adrenic acid (P-18:0/22:4), the preferred lipid substrate for lipid peroxidation and ferroptosis. Using congenic mice and nephrotoxic serum-induced immune complex glomerulonephritis model, we show that conditional deletion of heavy chain ferritin (FtH1) in the proximal tubules exacerbates ferroptosis and tubular injury. These findings were recapitulated by knocking down FtH1 in human proximal tubular cells and underscore the critical role of iron and heavy chain ferritin in tubular injury during the evolution of glomerulonephritis. Of translational relevance, Liproxstatin-2, a novel second-generation ferroptosis inhibitor, prophylactically and therapeutically mitigated lupus nephritis patient serum-induced ferroptosis in human proximal tubular cells. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in lupus nephritis.