Ferritin in Kidney and Vascular Related Diseases: Novel Roles for an Old Player

Abstract

Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous pathways and proteins have evolved to minimize the potential hazardous effects of iron cations and yet allow for readily available iron cations in a wide variety of fundamental metabolic processes. One of the extensively studied proteins in the context of systemic and cellular iron metabolisms is ferritin. While clinicians utilize serum ferritin to monitor body iron stores and inflammation, it is important to note that the vast majority of ferritin is located intracellularly. Intracellular ferritin is made of two different subunits (heavy and light chain) and plays an imperative role as a safe iron depot. In the past couple of decades our understanding of ferritin biology has remarkably improved. Additionally, a significant body of evidence has emerged describing the significance of the kidney in iron trafficking and homeostasis. Here, we briefly discuss some of the most important findings that relate to the role of iron and ferritin heavy chain in the context of kidney-related diseases and, in particular, vascular calcification, which is a frequent complication of chronic kidney disease.

Keywords: acute kidney injury; chronic kidney disease; ferritin; iron; vascular calcification.

Figure 1

Overall schematic of the proposed mechanism of the inhibition of VSMC calcification via the upregulation of FtH. The figure depicts a vascular smooth muscle cell (VSMC) where elevated levels of Pi (phosphorus) induce the upregulation of cbfa-1 (core binding factor alpha-1), leading to the deposition of extracellular Ca/Pi (hydroxyapatite crystals) and the activation of osteoblastic genes, including OC (osteocalcin) and ALP (alkaline phosphatase). This process can be exacerbated by the deletion of FtH (ferritin heavy chain) or mitigated via D3T (3H-1,2-Dithiole-3-thione) and Fe (iron)-induced FtH upregulation. There may still be novel genes and pathways modulated by FtH expression that require further investigations.