title: Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus.
abstract: The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells. The primary objective of this study was to determine the intracellular localization of this iron in the proximal tubule cell and to assess its potential toxicity. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice. Energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy were used to perform elemental analysis of these deposits and demonstrated that these deposits were iron rich. These deposits were associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Vitamin E administration to Hp 2-2 DM mice resulted in a significant decrease in both intralysosomal iron-induced oxidation and lysosomal destabilization. Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease.
authors: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 1 Efron St. Bat Galim, POB 9649, Haifa, Israel. asl@yahoo.com
authors: Rabea
authors: R
authors: Asleh
authors: Farid M
authors: FM
authors: Nakhoul
authors: Rachel
authors: R
authors: Miller-Lotan
authors: Hoda
authors: H
authors: Awad
authors: Dan
authors: D
authors: Farbstein
authors: Nina S
authors: NS
authors: Levy
authors: Nakhoul
authors: N
authors: Nakhoul
authors: Theodore C
authors: TC
authors: Iancu
authors: Irena
authors: I
authors: Manov
authors: Michael
authors: M
authors: Laue
authors: Maret G
authors: MG
authors: Traber
authors: Katie M
authors: KM
authors: Lebold
authors: Andrew P
authors: AP
authors: Levy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D007425:Intracellular Membranes; D007501:Iron / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006242:Haptoglobins; D014810:Vitamin E; D007501:Iron; D001619:beta-N-Acetylhexosaminidases