Pathogenesis of renal injury and hypertension in HIV+ children

项目总结/摘要 以往的研究表明，肾素血管紧张素系统（RAS）调节HIV-肾功能衰竭的结局， 疾病然而，HIV相关性肾病（HIVAN）的一个独特特征是在治疗期间没有高血压。 其早期阶段。这是一个有趣的发现，考虑到RAS似乎被激活， 非洲血统经常发展高血压慢性肾脏疾病（CKD）。在过去的六年里，我们 对约190名接受抗逆转录病毒治疗的艾滋病病毒感染儿童和青少年（CALWH）进行了随访 (ART)，并发现尽管存在高血压的主要危险因素， 直到HIV-CKD晚期才增加。因此，需要回答的一个关键问题是， 为什么经历HIV-CKD早期阶段的CALWH尽管有激活的高血压， RAS。我们在年轻的HIV-Tg 26小鼠中的初步数据表明，肾RAS被激活主要是为了抵消 HIV-细胞因子环境的过度作用，以及与之相关的盐耗障碍的存在， 随着蛋白尿和肾小管间质病变的发展。此外，我们发现跨膜（TM）- TNF-α、HIV-Tat和FGF-2在此过程中起关键作用。我们的数据强调了了解 RAS与HIV-细胞因子环境相互作用，因为RAS抑制剂通常用于伴有蛋白尿的CALWH 并且它们可以降低血压和损害肾灌注。在这里，我们假设艾滋病毒- 细胞因子环境破坏了肾RAS对条件产生适当反应的能力 这代表在婴儿期维持体内平衡和/或肾灌注的生理威胁。第二 这一假说的一个推论是，这些事件影响了产生肾素的细胞的可塑性， 对成年后患慢性肾病或高血压有长期影响。 使用时间和细胞特异性条件性缺失方法，以及单细胞转录组学分析，我们将测试 这个假设有三个目的。在目标1中，我们将定义HIV-细胞因子环境如何调节细胞因子的活性。 在儿童期内稳态受到饮食Na+或K+耗竭威胁的情况下，肾RAS。在 目的2：我们将确定RAS如何调节CD 4 + T细胞/巨噬细胞、足细胞和 肾小管上皮细胞培养的CALWH，并确定如何HIV-Tat影响肾RAS活性， HIV-Tg 26小鼠。在目标3中，我们将确定HIV-细胞因子环境如何影响肾小动脉的结构 和肾小管，以及产生肾素的细胞的转录组谱，在肾功能不全的情况下， RAS在婴儿期被血管紧张素转换酶抑制剂（ACEI）长期抑制。积极成果 将在CALWH中对ACEI治疗高血压和/或蛋白尿的ART进行验证。这些研究将 阐明HIV-细胞因子环境“程序化”肾小动脉反应的新机制， 肾小管对饮食电解质的变化以及长期使用ACEI，发现沉默的新生物标志物 肾缺血，并产生新的知识，以防止慢性肾脏病的进展，在CALWH。

PROJECT SUMMARY/ABSTRACT Previous studies have shown that the renin angiotensin system (RAS) modulates the outcome of HIV-kidney diseases. However, a unique feature of HIV-associated nephropathy (HIVAN) is the lack of hypertension during its early stages. This is an intriguing finding considering that the RAS appears to be activated, and people of African ancestry frequently develop hypertensive chronic kidney diseases (CKD). During the last six years we have followed the outcome of ~ 190 children and adolescents living with HIV (CALWH) on antiretroviral therapy (ART), and found that despite the presence of major risk factors for hypertension the prevalence of hypertension was not increased until the late stages of HIV-CKD. Therefore, a critical question that needs to be answered is why CALWH undergoing the early stages of HIV-CKD do not develop hypertension despite having an activated RAS. Our preliminary data in young HIV-Tg26 mice suggest that the renal RAS is activated mainly to counteract the hypotensive effects of the HIV-cytokine milieu, as well as the presence of salt wasting disorders associated with the development of proteinuria and tubulo-interstitial lesions. In addition, we found that transmembrane (tm)- TNF-α HIV-Tat, and FGF-2 play a critical role in this process. Our data highlight the need to understand how the RAS interacts with the HIV-cytokine milieu, since RAS inhibitors are used routinely in CALWH with proteinuria and they can lower the blood pressure and impair the renal perfusion. Here, we hypothesize that the HIV- cytokine milieu disrupts the ability of the renal RAS to mount a proper response to conditions representing a physiological threat to maintain homeostasis and/or renal perfusion in infancy. A second corollary of this hypothesis is that these events affect the plasticity of renin producing cells, and may have long-term consequences for developing chronic kidney diseases or hypertension in adulthood. Using time and cell specific conditional deletion approaches, and single cell transcriptomic analysis, we will test this hypothesis in three aims. In aim 1 we will define how the HIV-cytokine milieu modulates the activity of the renal RAS under conditions in which homeostasis is threatened in childhood by dietary Na+ or K+ depletion. In aim 2 we will determine how the RAS modulates the infection of CD4+ T cells / macrophages, podocytes and renal tubular epithelial cells cultured from CALWH, and determine how HIV-Tat affects the renal RAS activity in HIV-Tg26 mice. In aim 3, we will determine how the HIV-cytokine milieu affects the structure of renal arterioles and tubules, as well as the transcriptome profile of renin producing cells, under conditions in which the renal RAS is suppressed long term by angiotensin converting enzyme inhibitors (ACEI) during infancy. Positive results will be validated in CALWH on ART treated with ACEI for hypertension and/or proteinuria. These studies will elucidate new mechanisms whereby the HIV-cytokine milieu “programs” the response of renal arterioles and tubules to changes in dietary electrolytes as well as the long-term use of ACEI, discover new biomarkers of silent renal ischemia, and generate new knowledge to prevent the progression of CKD in CALWH.