Poly(Adenosine 5′-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy
Poly(Adenosine 5′-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy
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DOI：
10.1210/en.2009-0628
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Obrosova, Irina G.
中科院分区：
文献类型：
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作者：
Drel, Viktor R.;Xu, Weizheng;Obrosova, Irina G.
本研究旨在评价聚腺苷二磷酸核糖聚合酶(PARP)在1型糖尿病早期肾病中的作用。对照组和链脲佐菌素-糖尿病大鼠分别给予或不给予1，5-异喹啉二醇(1，5-异喹啉二醇)和10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1，2-diaza-benzo[de]-3-酮(GPI-15427)3 mg/kg(-1)治疗。D(-1)ip和30 mg/kg(-1)。D(-1)，连续10wk，第1次2wk后不治疗。免疫组织化学和蛋白质印迹分析检测肾皮质PARP活性。采用酶联免疫吸附试验、免疫印迹分析、免疫组织化学和比色法对糖尿病肾病患者的尿液和肾皮质指标进行评价。糖尿病大鼠的尿白蛋白排泄量增加了约4倍，这种增加可以被ISO和GPI-15427阻止。PARP抑制可抵消糖尿病相关肾小球和肾小管中多聚ADP核糖免疫反应性的增加以及多聚ADP核糖蛋白水平的增加。糖尿病大鼠肾组织中转化生长因子-β(1)、血管内皮生长因子、内皮素-1、肿瘤坏死因子-α、单核细胞趋化蛋白-1、脂质过氧化产物和硝基酪氨酸含量均升高，而异硫氰酸甘油酯和葛根素-15427可完全或部分阻止上述变化及尿肿瘤坏死因子-α排泄量的增加。抑制PARP可对抗糖尿病引起的内皮素(B)受体上调、足细胞丢失、肾皮质中α1胶原蛋白(IY)、高碘酸席夫阳性物质、纤维连接蛋白和晚期糖基化终末产物的积聚。综上所述，PARP激活与1型糖尿病相关的早期肾病的多种改变有关。这些发现为开发和进一步研究PARP抑制剂和含有PARP抑制剂的联合疗法提供了理论基础。(内分泌学150：5273-5283,2009)
This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg(-1) . d(-1) ip and 30 mg/kg(-1) . d(-1), respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-beta(1), vascular endothelial growth factor, endothelin-1, TNF-alpha, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-alpha excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-alpha 1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies. (Endocrinology 150: 5273-5283, 2009)