Renal Tubular Cell Ferroptosis: A New Player in Pathogenesis of Lupus Nephritis

Abstract

Background New research indicates that the injury to the renal tubular epithelial cells is a better predictor of renal outcomes in lupus nephritis (LN) as compared to glomerular injury. Iron accumulates mostly in the renal tubular cells of LN patients and murine models of LN. Ferroptosis is an incompletely understood form of cell death involving iron mediated lipid peroxidation, but its role in LN is not well established. Experiment LN and control patient biopsies were stained for markers of ferroptosis. Kidneys of female (MRL/lpr) and male (NZW X BXSB) F1, lupus mice were analyzed for markers of ferroptosis. Human proximal tubular cells (PTEC) were treated with LN serum with or without Liporxstatin-2, a novel ferroptosis inhibitor. Results Compared to controls, LN patients expressed higher levels of ACSL4 and 4HNE, the ferroptosis core proteins in the renal tubules. Compared to non-nephritic mice, nephritic mice had significantly higher gene expression of Aifm2, Acsl4, and Gpx1 as well as protein levels of Acsl4. Nephritic mice had an impaired renal glutathione synthesis pathway. Glutathione is an essential positive regulator of glutathione peroxidase 4 (Gpx4: ferroptosis inhibitor) which resulted in lower protein expression of Gpx4. Collectively, LN kidneys displayed a ferroptosis signature and was associated with an increase in Ngal and Kim1, PTEC injury markers. LN patients’ serum induced PTEC ferroptosis and associated pathology were significantly reduced by Liproxstatin-2. Conclusion Our data identify occurrence ferroptosis in renal tubular cell which can contribute to the pathogenesis of LN. Liproxstatin-2 mitigates human LN serum induced PTEC pathology and holds promise as an adjunct therapy to alleviate LN severity. Supported by grants from Vifor Pharma