Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model.
Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model.
复制标题
DOI：
10.1016/j.bcp.2009.11.018
复制
发表时间：
2010-04-01
影响因子：
5.8
通讯作者：
Obrosova, Irina G.
中科院分区：
文献类型：
--
作者：
Shevalye, Hanna;Stavniichuk, Roman;Xu, Weizheng;Zhang, Jie;Lupachyk, Sergey;Maksimchyk, Yury;Drel, Viktor R.;Floyd, Elizabeth Z.;Slusher, Barbara;Obrosova, Irina G.
关键词：
聚（ADP-核糖）聚合酶（PARP）在糖尿病肾病发病机制中的重要作用的证据正在出现。我们以前报道过PARP抑制剂可对抗早期1型糖尿病肾病。这项研究评估了PARP在长期1型糖尿病肾病中的作用。对照组和链脲佐菌素糖尿病大鼠在接受或不接受PARP抑制剂10-（4-甲基-哌嗪-1-基甲基）-2H-7-氧杂-1，2-二氮杂-苯并[de]蒽-3-酮（GPI-15，427，Eisai Inc.）治疗的情况下维持，30 mg kg−1d−1，在前2周未治疗后持续26周。通过聚（ADP-核糖基）化蛋白的Western印迹分析评估肾皮质中的PARP活性。采用ELISA法测定尿白蛋白、异前列腺素和8-羟基-2 ′-脱氧鸟苷排泄量，以及转化生长因子-β1、血管内皮生长因子、可溶性细胞间粘附分子-1、纤连蛋白和硝基酪氨酸的肾脏浓度，采用比色法测定尿肌酐和肾脏脂质过氧化产物。PARP抑制抵消了糖尿病相关的肾皮质聚（ADP-核糖基）化蛋白水平的增加。糖尿病大鼠的尿白蛋白、异前列腺素和8-羟基-2 ′-脱氧鸟苷排泄量以及尿白蛋白/肌酐比值增加，GPI-15，427治疗至少部分预防了所有这些变化。PARP抑制可抵消糖尿病诱导的肾脏转化生长因子-β1、血管内皮生长因子和纤连蛋白的蓄积，但不能抵消可溶性细胞间粘附分子-1和硝基酪氨酸的蓄积。脂质过氧化产物浓度在对照组和用或不用GPI-15，427治疗的糖尿病大鼠中是不可区分的。总之，PARP激活在长期糖尿病肾病中起重要作用。这些发现为开发和进一步研究PARP抑制剂和含PARP抑制剂的联合疗法预防和治疗糖尿病肾病提供了理论基础。
Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30 mg kg−1d−1, for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2′-deoxyguanosine excretion, and renal concentrations of transforming growth factor-β1, vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays. PARP inhibition counteracted diabetes-associated increase in renal cortex poly(ADP-ribosyl)ated protein level. Urinary albumin, isoprostane, and 8-hydroxy-2′-deoxyguanosine excretions and urinary albumin/creatinine ratio were increased in diabetic rats, and all these changes were at least partially prevented by GPI-15,427 treatment. PARP inhibition counteracted diabetes-induced renal transforming growth factor-β1, vascular endothelial growth factor, and fibronectin, but not soluble intercellular adhesion molecule-1 and nitrotyrosine, accumulations. Lipid peroxidation product concentrations were indistinguishable among control and diabetic rats maintained with or without GPI-15,427 treatment. In conclusion, PARP activation plays an important role in kidney disease in long-term diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies, for prevention and treatment of diabetic nephropathy.
登录
查看更多内容
影响因子：
4.8
作者：
Drel, Viktor R.;Xu, Weizheng;Obrosova, Irina G.
通讯作者：
Obrosova, Irina G.
影响因子：
4.8
作者：
Forbes, JM;Thallas, V;Cooper, ME
通讯作者：
Cooper, ME
影响因子：
--
作者：
Dan, QH;Wong, RLC;Lam, KSL
通讯作者：
Lam, KSL
对糖尿病性肾病中纤维化和硬化症机制的新见解。
影响因子：
8.2
作者：
Brosius, Frank C., III
通讯作者：
Brosius, Frank C., III
DOI：
10.1152/ajprenal.90326.2008
发表时间：
2009-02-01
影响因子：
4.2
作者：
Garman, Joseph H.;Mulroney, Susan;Maric, Christine
通讯作者：
Maric, Christine