Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus.
Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus.
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DOI：
10.1016/j.freeradbiomed.2012.06.015
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发表时间：
2012-08-15
影响因子：
7.4
通讯作者：
Levy, Andrew P.
中科院分区：
文献类型：
--
作者：
Asleh, Rabea;Nakhoul, Farid M.;Miller-Lotan, Rachel;Awad, Hoda;Farbstein, Dan;Levy, Nina S.;Nakhoul, Nakhoul;Iancu, Theodore C.;Manov, Irena;Laue, Michael;Traber, Maret G.;Lebold, Katie M.;Levy, Andrew P.
结合珠蛋白(HP)基因是糖尿病(DM)患者肾病进展的主要决定因素。Hp蛋白的主要功能是结合和调节体外血红蛋白及其铁载体的命运。我们之前已经证明了Hp基因和DM之间的相互作用对肾脏近端小管细胞中铁的积累有影响。这项研究的主要目的是确定这种铁在近端小管细胞内的定位，并评估其潜在的毒性。透射电子显微镜显示HP2-2 DM小鼠近端肾小管细胞溶酶体内有明显的电子致密沉积。用能量色散X射线能谱和电子能量损失谱对这些沉积物进行了元素分析，证明这些沉积物是富铁的。这些沉积与溶酶体膜脂质过氧化和溶酶体膜完整性丧失有关。给予HP2-2 DM小鼠维生素E可显著降低溶酶体内铁诱导的氧化和溶酶体失稳。铁诱导的肾小管损伤可能在糖尿病肾病的发展中起主要作用，并可能成为减缓肾脏疾病进展的靶点。
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.
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影响因子：
7.7
作者：
Asleh R;Blum S;Kalet-Litman S;Alshiek J;Miller-Lotan R;Asaf R;Rock W;Aviram M;Milman U;Shapira C;Abassi Z;Levy AP
通讯作者：
Levy AP
DOI：
10.1161/01.atv.0000251020.24399.a2
发表时间：
2007-01-01
影响因子：
8.7
作者：
Levy, Andrew P.;Levy, Joanne E.;Moreno, Pedro R.
通讯作者：
Moreno, Pedro R.
影响因子：
7.7
作者：
Costacou T;Ferrell RE;Ellis D;Orchard TJ
通讯作者：
Orchard TJ
影响因子：
--
作者：
Cilensek, Ines;Mankoc, Sara;Petrovic, Daniel
通讯作者：
Petrovic, Daniel
影响因子：
3.3
作者：
Pezzolesi, Marcus G.;Skupien, Jan;Mychaleckyj, Josyf C.;Warram, James H.;Krolewski, Andrzej S.
通讯作者：
Krolewski, Andrzej S.