Long-term effects of acute renal failure

描述(由申请人提供)：急性肾损伤(AKI)是诱发慢性肾脏疾病(CKD)的一个重要因素，但其关系的性质尚不清楚。我们证明，在大鼠肾缺血再灌注(I/R)诱导的急性肾损伤后，肾毛细血管密度受到永久性损害。AKI改变肾脏血流动力学反应，易患盐敏感型高血压，我们证明I/R后保留血管结构可减轻高盐诱导的CKD。然而，免疫抑制也阻止了盐诱导的高血压和AKI后的CKD。此外，对单侧AKI后对侧肾脏(称为“远端/间接”AKI)的初步研究表明，在没有直接损伤的情况下，循环因素改变了血流动力学功能。我们的主要假设是，AKI通过血管丢失和T淋巴细胞的激活和分化改变慢性肾功能，这两种细胞在促进高血压和CKD方面具有独立和协同的作用。大鼠将在“直接AKI”和“远程AKI”模型中进行研究，同时减少肾脏质量和高盐饮食。具体目标1将检验这样一种假设，即AKI促进T细胞的持续沉积，其细胞因子谱受损伤类型(直接与远程)、肾脏质量减少和饮食盐的调节。这些研究将 利用FACS分析，通过评估T细胞产生的细胞因子谱和损伤后抗原提呈细胞的激活来表征辅助性T细胞的分化。特定目标2将检验AKI激活的淋巴细胞影响肾血流动力学功能、直接或远程肾损伤后高血压和慢性肾脏病的假说。这些研究将利用免疫抑制和过继转移两种方法来评估血流动力学控制的变化。进一步的研究将通过过继转移到受损或非受损的T细胞缺陷RAS来评估AKI和损伤激活的T细胞在盐诱导的CKD中的不同和协同作用。最后，特殊目标3将评估高盐饮食(直接损伤后)诱导T细胞分化是AKI向CK转变的关键步骤的假说。这些研究将使用策略来阻断特定的协同刺激和趋化因子通路，这些通路可能特定地增强T细胞分化，并确定常用的降压治疗是否影响AKI后高盐死亡后的T细胞分化。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the nature of the relationship is not clear. We demonstrated that renal capillary density is permanently compromised in rats following AKI induced by ischemia reperfusion (I/R). AKI alters renal hemodynamic responses and predisposes to salt- sensitive hypertension and we demonstrated that preservation of vascular structure following I/R attenuates high-salt induced CKD. However, immunosuppression also blocked salt-induced hypertension and CKD following AKI. Moreover, preliminary studies on the contralateral kidney following unilateral AKI (termed "remote/indirect" AKI) demonstrates that circulating factors alter hemodynamic function in the absence of direct injury. Our overarching hypothesis is that AKI alters chronic renal function due to vascular dropout and activation and differentiation of T lymphocytes, which have independent and synergistic effects to promote hypertension and CKD. Rats will be studied in models of "direct AKI" injury and "remote AKI" in combination with reduced renal mass and high salt diet. Specific aim 1 will test the hypothesis that AKI promotes the persistent deposition of T cells and their cytokine profiles are modulated by the type of injury (direct vs. remote), reduced renal mass, and dietary salt. These studies will utilize FACS analysis and characterize T helper differentiation by assessing cytokine profiles produced by T-cells, and the activation of antigen presenting cells following injury. Specific aim 2 will test the hypothesis that AKI primed lymphocytes influence renal hemodynamic function, hypertension and CKD following direct or remote renal injury. These studies will utilize both immunosuppressive and adoptive transfer approaches to evaluate alterations in hemodynamic control. Additional studies using adoptive transfer into injured or non-injured T cell deficient ras will be used to evaluate the distinct and synergistic interactions of AKI and injury activated T cells on salt induced CKD. Finally, Specific aim 3 will evaluate the hypothesis that T cell differentiation induced by high salt diet (following direct injury), is a key step in the AKI to CK transition. These studies will use strategies to block specific co-stimulatory and chemokine pathways which may specifically enhanced T cell differentiation and determine if commonly utilized anti-hypertensive treatments influence T-cell differentiation in response to high salt die following AKI.