Pathogenesis of renal injury and hypertension in HIV+ children

HIV儿童肾损伤和高血压的发病机制

• 批准号: 10700601
• 负责人: PATRICIO E RAY
• 金额: $ 68.01万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700601
• 关键词: AIDS-Associated Nephropathy; Adolescent; Adult; Affect; African ancestry; Angiotensin-Converting Enzyme Inhibitors; Annexins; Biological Markers; Black race; Blood Pressure; CD4 Positive T Lymphocytes; Cardiovascular system; Cells; Child; Childhood; Chronic; Chronic Kidney Failure; Data; Development; Electrolyte Balance; Electrolytes; Enalapril; Epithelial Cells; Equilibrium; Event; FGF2 gene; FRS2 gene; Fibroblast Growth Factor; Fluid Balance; HIV; Homeostasis; Hypertension; Hypotension; Hypotensives; Impairment; Infection; Inflammatory; Injury to Kidney; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Lesion; Life; Macrophage; Mediating; Membrane; Modeling; Monitor; Mononuclear; Mus; Outcome; Pathogenesis; Pathway interactions; Perfusion; Persons; Physiological; Play; Prevalence; Process; Protein Secretion; Proteins; Proteinuria; Renal Hypertension; Renin; Renin-Angiotensin System; Risk Factors; Role; Signal Transduction; Sodium Chloride; Structure; TNF gene; Tamoxifen; Testing; Tubular formation; Viral; Wasting Syndrome; Water; antiretroviral therapy; arteriole; blood pressure reduction; cytokine; dietary; hypertensive; infancy; inhibitor; kidney vascular structure; particle; podocyte; prevent; programs; receptor; renal epithelium; renal ischemia; response; time use; transcriptome; transcriptomics

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.

项目概要/摘要 先前的研究表明，肾素血管紧张素系统 (RAS) 调节 HIV 肾脏的结果 然而，HIV 相关肾病 (HIVAN) 的一个独特特征是在治疗期间没有高血压。 考虑到 RAS 似乎已被激活，而且人们还处于早期阶段，这是一个有趣的发现。 非洲血统在过去六年中经常患高血压慢性肾病（CKD）。 跟踪了约 190 名艾滋病毒感染者 (CALWH) 儿童和青少年的抗逆转录病毒治疗结果 （ART），发现尽管存在高血压的主要危险因素，但高血压的患病率 直到 HIV-CKD 晚期才增加。因此，需要回答的一个关键问题是。 为什么处于 HIV-CKD 早期阶段的 CALWH 尽管具有激活的 RAS。我们在年轻 HIV-Tg26 小鼠中的初步数据表明，肾 RAS 被激活主要是为了抵消。 HIV 细胞因子环境的低血压作用，以及相关盐消耗障碍的存在 随着蛋白尿和肾小管间质病变的发展，我们发现跨膜（tm）-。 TNF-α HIV-Tat 和 FGF-2 在此过程中发挥着关键作用，我们的数据强调需要了解如何发挥作用。 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 它们可以降低血压并损害肾脏灌注。 细胞因子环境破坏肾 RAS 对状况做出适当反应的能力 代表对维持婴儿期体内平衡和/或肾灌注的生理威胁。 该假设的推论是这些事件影响肾素产生细胞的可塑性，并且可能 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删除方法以及单细胞转录组分析，我们将测试 在目标 1 中，我们将定义 HIV 细胞因子环境如何调节 HIV 细胞因子的活性。 在儿童时期体内稳态因膳食 Na+ 或 K+ 消耗而受到威胁的情况下，肾脏 RAS 发生变化。 目标 2 我们将确定 RAS 如何调节 CD4+ T 细胞/巨噬细胞、足细胞和 从 CALWH 培养的肾小管上皮细胞，并确定 HIV-Tat 如何影响肾 RAS 活性 HIV-Tg26 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，以及肾素产生细胞的转录组谱，在肾 婴儿期 RAS 受到血管紧张素转换抑制剂酶 (ACEI) 的长期抑制。 将在 CALWH 中对使用 ACEI 治疗高血压和/或蛋白尿的 ART 进行验证。 阐明 HIV 细胞因子环境“编程”肾小动脉反应的新机制 肾小管对饮食电解质变化以及长期使用 ACEI 的影响，发现沉默的新生物标志物 肾缺血，并产生新的知识来预防 CALWH 中 CKD 的进展。