MECHANISMS OF RADIATION-INDUCED KIDNEY INJURY

描述：（改编自申请人摘要）：辐射诱导 肾损伤是放射治疗的主要并发症，特别是在 接受骨髓全身照射的患者 移植 肾病可能进展为终末期肾病。 由于越来越多的骨髓移植手术， 放射性肾病的特征和预防进展是 主要关注点。 我们对伤病的理解有很大的差距， 导致其发展到不可逆阶段。 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。 肾小球瘢痕形成表明 促进纤维形成的因子的表达和合成。 另 另一方面，肾小球毛细血管内皮的损伤可能表明， 内皮衍生因子的合成可能因此受到干扰 引起肾血流动力学损害。 我们已经证明血管紧张素II (AII)合成抑制剂保护大鼠肾功能和结构 放射性肾病模型。 这意味着生物事件触发了 作为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（TGF）-β 1与内皮源性 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，以检验以下假设： 1)在放射性肾病中， 细胞外基质（ECM）蛋白和增强表达TGF-β 1， 促进这些ECM蛋白的合成。 AII抑制减弱TGF-β 1 ECM蛋白的表达和合成。 2)在辐射诱导 肾病存在肾小球毛细血管内皮损伤。 这 导致内皮衍生的血管扩张剂的产生受损， 一氧化氮（NO），从而改变肾小球中的压力和流量 微脉管系统 AII合成抑制恢复或促进NO 生成，从而改善肾缺血。 预计该 观察将增强我们对 辐射引起的伤害，并提供手段，以避免其发展， 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.