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-a 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.