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Iron-mediated retinal degeneration in hemojuvelin knockout mice. Biochem J. 2011 Sep 26; Authors: Gnana-Prakasam JP, Tawfik A, Romej M, Ananth S, Martin PM, Smith SB, Ganapathy V Abstract
Hemochromatosis is a genetic disorder of iron overload resulting from loss-of-function mutations in genes coding for the iron-regulatory proteins HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin (HJV). Recent studies have established the expression of all the five genes in retina, indicating their importance in retinal iron homeostasis. We previously demonstrated that Hjv is expressed in retinal pigment epithelium (RPE), outer and inner nuclear layers, and ganglion cell layer. Here we report on the consequences of Hjv deletion on the retina in mice. Hjv-null mice at ³18 months of age had increased iron accumulation in retina with marked morphological damage compared to age-matched controls; these changes were not found in younger mice. The retinal phenotype in Hjv-null mice included hyperplasia of RPE. We isolated RPE cells from wild type and Hjv-null mice and examined their growth patterns. Hjv-null RPE cells were less senescent and exhibited a hyperproliferative phenotype. Hjv-null RPE cells also showed upregulation of Slc7a11 that codes for the 'transporter proper' subunit xCT in the heterodimeric amino acid transporter cystine/glutamate exchanger (xCT/4F2hc). Bone morphogenic protein (BMP) 6 could not induce hepcidin expression in Hjv-null RPE cells, confirming that retinal cells require Hjv for induction of hepcidin via BMP6 signaling. Hjv is a glycosylphosphatidylinositol-anchored protein, and the membrane-associated Hjv is necessary for BMP6-mediated activation of hepcidin promoter in RPE cells. Taken together, these studies confirm the biological importance of Hjv in the regulation of iron homeostasis in the retina and in RPE.
PMID: 21943374 [PubMed - as supplied by publisher] Read more |
