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(Journal Article): Regulation of transferrin receptor 2 by transferrin: diferric transferrin regulates transferrin receptor 2 protein stability
Johnson MB, Enns CA
IN:
Blood
2004; Epub(19)
Impact Factor(s) of Blood: 9.782 (2004), 10.12 (2003), 9.631 (2002), 9.273 (2001)
Fulltext: HTML
ABSTRACT: Transferrin receptor 2 (TfR2) is a type-II transmembrane protein expressed in hepatocytes that binds iron-bound transferrin (Tf). Mutations in TfR2 cause one form of hereditary hemochromatosis, a disease in which excessive absorption of dietary iron can lead to liver cirrhosis, diabetes, arthritis, and heart failure. The function of TfR2 in iron homeostasis is unknown. We have studied the regulation of TfR2 in HepG2 cells. Western blot analysis shows that TfR2 increases in a time- and dose-dependent manner after addition of diferric Tf to the culture medium. In cells exposed to diferric Tf, the amount of TfR2 returns to control levels within 8 hours after removal of diferric Tf from the medium. However, TfR2 does not increase when non-Tf bound iron (FeNTA) or apoTf is added to the medium. The response to diferric Tf appears to be hepatocyte specific. Real-time qRT-PCR analysis shows that TfR2 mRNA levels do not change in cells exposed to diferric Tf. Rather, the increase in TfR2 is due to an increase in the half-life of TfR2 protein in cells exposed to diferric Tf. Our results support a role for TfR2 in monitoring iron levels by sensing changes in the concentration of diferric Tf.
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(Journal Article): Functional, molecular, and biochemical characterization of streptozotocin-induced diabetes.
Ward DT, Yau SK, Mee AP, Mawer EB, Miller CA, Garland HO, Riccardi D (School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.)
IN:
J Am Soc Nephrol
2001; 12:779-790
Impact Factor(s) of J Am Soc Nephrol: 6.644 (2004), 7.499 (2003), 6.337 (2001)
ABSTRACT: Altered divalent cation homeostasis with bone mineral loss, hypercalciuria, and hypomagnesemia have been associated consistently with human diabetes mellitus. This study investigated functional, molecular, and biochemical determinants that accompany this condition in chronically (2 wk) streptozotocin (STZ)-diabetic rats. Catheterized, conscious, diabetic rats on servo-controlled fluid replacement exhibited an increased GFR (+70%) and a substantially raised urinary calcium output (+568%) when compared with control rats. In addition, fractional calcium reabsorption was reduced, indicating that the hypercalciuria was not due solely to an osmotic effect but may involve an actual tubular defect. The expression of proteins involved in renal distal Ca2+ and water transport in STZ-diabetic rats were then studied by Western analysis and immunofluorescence microscopy to investigate the molecular basis of the hypercalciuria. Extracellular Ca2+-sensing receptor abundance was reduced to 52% of control in STZ-diabetes, whereas thiazide-sensitive NaCl cotransporter expression was increased by 192%. Subcutaneous insulin implant rectified both functional and molecular parameters. The levels of calbindin D(28k), plasma membrane Ca2+ ATPase, and aquaporin 1 in whole kidney and of aquaporin 2 in inner medulla were unchanged in diabetic and/or insulin replacement. Blood levels of 1,25(OH)(2)D(3) were reduced in diabetes as were levels of osteocalcin, a marker of bone formation. It is concluded that diabetic hypercalciuria in rats involves elevated GFR with raised urinary output, reduced Ca2+ reabsorption, and impaired bone deposition. Changes in Ca2+-sensing receptor and NaCl cotransporter protein expression could account for the altered divalent cation homeostasis seen during diabetes mellitus.
TYPE OF PUBLICATION: Original article
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