Iron metabolism in the pathogenesis of iron-induced kidney injury

Abstract

In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

“…It has also been shown that AKI increases intracellular levels of free catalytic iron, which increases oxidative stress and renal injury after IR-AKI (35). Moreover, acetaminophen, which inhibits iron-catalyzed lipid peroxidation (7), attenuates serum and/or urinary isofuran/F2-isporsotane levels in patients with sepsis (27), and in patients undergoing cardiopulmonary bypass surgery (5,51).…”

“…Unlike other antioxidants, PM can scavenge different toxic RCS, including lipid peroxidation products (59,61), which contribute to tissue injury under conditions of oxidative stress (37,49). In addition, PM can sequester redox metal ions, including free iron, and inhibit their ability to catalyze multiple toxic oxidative pathways (35,58,60). Because PM therapy targets multiple oxidative reactions in vivo, in particular redox-active metal ions that amplify pathological stress responses, the beneficial effects of PM may occur at lower effective drug concentrations compared with those of antioxidants, like vitamin E and NAC.…”

“…The ability of PM to interfere with multiple aspects of oxidative stress is favorable for the treatment of AKI. In particular, there is extensive clinical and preclinical evidence that free iron contributes to the pathogenesis of AKI associated with crush injury (rhabdomyolysis) and ischemia-reperfusion-induced AKI (IR-AKI) (35), as well as AKI induced by sepsis and cardiac surgery (4,5,27). This suggests that free iron scavenging by PM may be advantageous for the treatment of AKI in a variety of different clinical scenarios.…”

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

“…In vivo in the steady state, absorbed iron is exported to the interstitium and capillary blood across the basolateral (BL) membrane of PT cells (6 -8). The transport of iron between different body, cell, and subcellular compartments is complicated because the known membrane transporters for iron (8) accept only the more soluble ferrous form (Fe 2ϩ ), whereas the majority of iron in the extracellular fluid and serum is in the more stable ferric form (Fe 3ϩ ) bound to either transferrin (Tf) or small molecules (non-Tf bound iron or NTBI). Hence, there is a need for iron redox enzymes close to the site of membrane transport (see Fig.…”

“…A similar reaction is likely to occur under pathological conditions when NTBI and/or hemin filtered through the glomeruli come in contact with PrP C on the plasma membrane of PT cells (8). To evaluate this possibility, PT cells expressing PrP C or PrP ⌬51-89 were exposed to hemin or FAC overnight, and lysates were subjected to Western blotting and probed for PrP and ␤-actin (Fig.…”