Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis

Abstract

Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

“…Higher concentrations of free iron and other iron-binding proteins in synovial fluid and infusion of iron-dextran increase lipid peroxidation, decrease red cell glutathione, and exacerbate RA synovitis ( 36 ). In SLE, increased dietary iron and iron infusion also exacerbate disease activity ( 37 ). However, it remains to be confirmed whether inhibiting ferroptosis could be beneficial in AIRDs ( 36 , 37 ).…”

“…In SLE, increased dietary iron and iron infusion also exacerbate disease activity ( 37 ). However, it remains to be confirmed whether inhibiting ferroptosis could be beneficial in AIRDs ( 36 , 37 ).…”

The Potential Role of Ferroptosis in Systemic Lupus Erythematosus

“…As mentioned above, renal iron accumulation occurs in LN and contributes to the development of albuminuria ( 12 ). RTECs reabsorb the majority of filtered iron ( 71 ), and these cells have been shown to undergo ferroptosis under pathological conditions ( 72 , 73 ). Treatment of lupus mice models with iron metabolism regulators, such as deferiprone and hepcidin, could mitigate kidney inflammation and delay lupus progression ( 12 , 22 ).…”

Iron Inhibits the Translation and Activity of the Renal Epithelial Sodium Channel

“…Renal iron metabolism is a complex process involving iron import, storage, and export [ 21 ]. Little is known about iron handling by glomerular cells and most of our understanding of renal iron handling is based on studies on the tubular compartment [ 22 , 23 ]. Proximal tubular epithelial cells (PTECs) express ZIP8, ZIP14, and DMT1 for iron import, light and heavy chain ferritin for iron storage, and ferroportin for iron export [ 24 ].…”

“…Hence, PTECs participate in renal iron recycling [ 24 ]. We and others have shown the importance of iron regulation in PTECs in the context of acute kidney injury (AKI) and fibrosis [ 23 , 25 , 26 ]. The distal renal tubules also express the proteins ZIP8, ZIP14, and DMT1 (iron import).…”