MECHANISMS OF RADIATION-INDUCED KIDNEY INJURY

描述：(改编自申请人的摘要)：辐射诱导 肾损伤是放射治疗的主要并发症，尤其是在 接受全身放射治疗的患者的骨髓 移植。肾病可进展为终末期肾病。 由于进行的骨髓移植数量不断增加， 放射性肾病的特征和进展的预防 最令人担忧的问题。我们对受伤的理解有很大的差距， 使其发展到不可逆转的阶段。细胞外基质 肾小球毛细血管合成(瘢痕形成)与内皮损伤 是关键特征。肾小球疤痕是强化的征兆 促进纤维化形成的因子的表达和合成。另一方面 另一方面，肾小球毛细血管内皮细胞的损伤可能表明 内皮衍生因子的合成可能因此而受到干扰 导致肾脏血流动力学受损。我们已经证明血管紧张素II 合成抑制对大鼠肾脏功能和结构的保护作用 放射性肾病模型。这意味着触发了生物事件 被认为是辐射发病机制的潜在机制 肾病。两个可能的事件是，ECM促进因子的合成 转化生长因子-β1与内皮源性细胞的生成 血管扩张剂，一氧化氮。拟议的研究将使用大鼠模型。 放射性肾病来检验以下假说： 1)在放射性肾病中，特异性的合成增强 细胞外基质蛋白与转化生长因子-β1的表达增强 促进这些细胞外基质蛋白质的合成。AII抑制作用减弱转化生长因子-β1 细胞外基质蛋白的表达和合成。2)在辐射诱导下 肾病有肾小球毛细血管内皮细胞损伤。这 导致内皮衍生血管扩张剂的产生受损， 一氧化氮(NO)，从而改变肾小球内的压力和流量 微血管系统。AII合成抑制可恢复或促进NO 产生，从而改善肾缺血。据预计， 观察将加深我们对肺炎的病理生物学的了解。 并提供手段以避免其进展到 不可逆转的阶段。

DESCRIPTION: (Adapted from the applicant's abstract): Radiation-induced renal injury is a major complication of radiotherapy, particularly in patients subjected to total body irradiation for bone marrow transplantation. The nephropathy may progress to end stage renal disease. Because of the growing number of bone marrow transplants performed, characterization and prevention of progression of radiation nephropathy is of major concern. There is a big gap in our understanding of the injury and causing its progression to irreversible stages. Extracellular matrix synthesis (scarring) in renal glomerular capillary and endothelial injury are key characteristics. Glomerular scarring is indicative of enhanced expression and synthesis of factors that promote fibrogenesis. On the other hand, injury of the glomerular capillary endothelium may indicate that the synthesis of endothelium-derived factors may become perturbed thereby causing renal hemodynamic impairment. We have shown that angiotensin II (AII) synthesis inhibition preserves renal function and structure in a rat model of radiation nephropathy. This implicates biologic events triggered by AII as potential mechanisms underlying the pathogenesis of radiation nephropathy. Two likely events are, synthesis of the ECM promoting factor Transformng Growth Factor (TGF)-b1 and generation of the endothelium-derived vasodilator, nitric oxide. The proposed studies will use a rat model of radiation nephropathy to test the following hypotheses: 1) In radiation-induced nephropathy there is enhanced synthesis of specific extracellular matrix (ECM) proteins and enhanced expression of TGF-b1 which promotes synthesis of these ECM proteins. AII inhibition attenuates TGF-b1 expression and synthesis of ECM proteins. 2) In radiation-induced nephropathy there is injury of the glomerular capillary endothelium. This results in impaired production of the endothelium-derived vasodilator, nitric oxide (NO), thereby changing pressures and flows in the glomerular microvasculature. AII synthesis inhibition restores or promotes NO generation thereby ameliorating renal ischemia. It is anticipated that the observations will enhance our understanding of the pathobiology of radiation-induced injury and provide means to avert its progression to irreversible stages.