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.

项目总结/文摘