Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus

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• 作者：Rabea Asleh ; Farid M. Nakhoul ; Rachel Miller-Lotan ; Hoda Awad ; Dan Farbstein ; Nina S. Levy ; Nakhoul Nakhoul ; Theodore C. Iancu ; Irena Manov ; Michael Laue ; Maret G. Traber ; Katie M. Lebold ; Andrew P. Levy
• 关键词：DN ; Diabetic nephropathy ; ESRD ; End-stage renal disease ; Hp ; Haptoglobin ; DM ; Diabetes mellitus ; EDC ; Epidemiology of diabetic complications ; DCCT/EDIC ; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ; TEM
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 出版时间：15 August, 2012
• 年：2012
• 卷：53
• 期：4
• 页码：779-786
• 全文大小：608 K

文摘

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.