Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy
Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy
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DOI：
10.1152/ajprenal.00088.2005
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发表时间：
2005-09-01
影响因子：
4.2
通讯作者：
Tesch, GH
中科院分区：
文献类型：
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作者：
de Haan, JB;Stefanovic, N;Tesch, GH
在许多疾病中，包括进行性肾病、组织损伤和病理性细胞内信号传导事件依赖于氧化应激。谷胱甘肽过氧化物酶-1（Gpx 1）是一种在肾脏中高度表达的抗氧化酶，可清除可导致肾损伤的过氧化物和过氧亚硝酸盐。因此，我们研究了这种丰富的肾脏抗氧化酶是否限制了1型糖尿病肾病发展过程中的肾损伤。通过连续2天腹腔注射链脲佐菌素（100 mg/kg）使野生型（Gpx 1 +/+）和缺陷型（Gpx 1-/-）小鼠患糖尿病。选择血糖水平相同（23 +/- 4 mM）的糖尿病Gpx 1 +/+和-/-小鼠，并在糖尿病4个月后进行检查。与正常小鼠相比，糖尿病Gpx 1 +/+和-/-小鼠在糖尿病2个月和4个月时尿白蛋白排泄增加2 - 3倍。在4个月时，糖尿病Gpx 1 +/+和-/-小鼠的氧化性肾损伤水平相当（肾脏活性氧、肾脏脂质过氧化、尿异前列腺素、晚期糖基氧化和亚硝基化终产物的肾脏沉积增加）和相似程度的肾小球损伤（肥大、细胞过多、硬化）、肾小管损伤（细胞凋亡和波形蛋白表达）和肾纤维化（肌成纤维细胞、胶原、TGF-β分泌）。糖尿病肾脏中Gpx 1的缺乏不能通过过氧化氢酶或其他Gpx亚型水平的增加来补偿。与预期相反，这项研究表明，在1型糖尿病模型中，肾脏中高水平表达的Gpx 1对肾脏氧化应激和肾病的发展没有保护作用。
In many diseases, including progressive renal disorders, tissue injury and pathological intracellular signaling events are dependent on oxidative stress. Glutathione peroxidase-1 (Gpx1) is an antioxidant enzyme that is highly expressed in the kidney and removes peroxides and peroxynitrite that can cause renal damage. Therefore, we examined whether this abundant renal antioxidant enzyme limits renal damage during the development of type 1 diabetic nephropathy. Wild-type (Gpx1+/+) and deficient (Gpx1-/-) mice were made diabetic by intraperitoneal injection of streptozotocin (100 mg/kg) on 2 consecutive days. Diabetic Gpx1+/+ and -/- mice with equivalent blood glucose levels (23 +/- 4 mM) were selected and examined after 4 mo of diabetes. Compared with normal mice, diabetic Gpx1+/+ and -/- mice had a two- to threefold increase in urine albumin excretion at 2 and 4 mo of diabetes. At 4 mo, diabetic Gpx1+/+ and -/- mice had equivalent levels of oxidative renal injury ( increased kidney reactive oxygen species, kidney lipid peroxidation, urine isoprostanes, kidney deposition of advanced glycoxidation, and nitrosylation end products) and a similar degree of glomerular damage ( hypertrophy, hypercellularity, sclerosis), tubular injury ( apoptosis and vimentin expression), and renal fibrosis (myofibroblasts, collagen, TGF-beta excretion). A lack of Gpx1 was not compensated for by increased levels of catalase or other Gpx isoforms in diabetic kidneys. Contrary to expectations, this study showed that the high level of Gpx1 expressed in the kidney is not protective against the development of renal oxidative stress and nephropathy in a model of type 1 diabetes.