Genetic Appraisal of RAAS-Associated SNPs: REN (rs16853055), AGT (rs3789678) and ACE (rs4305) in Preeclamptic Women Living with HIV Infection.

PURPOSE OF REVIEW: The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to the development of hypertension in preeclampsia. The secondary goal was to establish if there was a link between these SNPs and HIV infection. RECENT FINDINGS: There is a paucity of findings related to the aforementioned SNPs and preeclampsia. There are no recent findings on the rs16853055 renin polymorphism. The rs3789678 angiotensinogen polymorphism correlated significantly with gestational hypertension. The rs4305 ACE polymorphism showed no significant association with the development of pregnancy-induced hypertension. There are conflicting findings when determining the relationship between ethnicity and the predisposition of preeclampsia and hypertension in relation to the discussed RAAS-associated SNPs. To date, the association between RAAS-associated SNPs and preeclamptic women co-morbid with HIV in South Africa has revealed that certain alleles of the AGT gene are more prominent in HIV-infected PE compared to normotensive pregnant HIV-infected women.

Placental progesterone and its receptor in HIV-infected pre-eclamptic women.

Given the high prevalence of HIV infection and pre-eclampsia (PE) in South Africa, this study evaluated and compared the placental immunostaining of progesterone (P) and progesterone receptors (PR) in the synergy of HIV-infected PE compared to normotensive pregnant women using immunohistochemistry interfaced with morphometric image analysis. Progesterone immunostaining was expressed widely across exchange and conducting villi within mesenchymal, endothelial, and trophoblast cells. In contrast, PR was expressed within syncytiotrophoblasts and was absent within endothelial cells. In exchange villi, P and PR immuno-expression was significantly lower in PE compared to the normotensive group (p = < 0.0001 and p = < 0.0001, respectively) and within the early-onset pre-eclampsia (EOPE) compared to the late-onset pre-eclampsia (LOPE) group (p = < 0.0001 and p = < 0.0001, respectively). Progesterone immuno-expression was significantly lower in the HIV+ compared to the HIV- group (p = < 0.0001), whilst PR was non-significant. In conducting villi, P and PR immuno-expression was significantly lower in the EOPE compared to the LOPE group (p = < 0.0001 and p = < 0.0001, respectively) and in the HIV+ compared to the HIV- group (p = < 0.0001 and p = 0.0009, respectively). Progesterone immuno-expression was slightly higher in the PE compared to normotensive group, and PR immuno-expression was non-significant. There was a significant difference between P and PR within exchange versus conducting villi regardless of pregnancy type, with villi type accounting for 34.47% and 15.28% of total variance for P and PR, respectively. Placental P and PR immuno-expression is downregulated in the duality of PE and HIV+ infection. The use of combined antiretroviral therapy (cART) may result in defective P synthesis, which causes insufficient binding to its receptors. Consequently, PI3K/AKT, JAK-STAT, and MAPK signalling pathways are affected, impairing trophoblast invasion and leading to pre-eclampsia development. Notably, the decrease in P and PR immuno-expression in EOPE validates their effect on placentation.

Is the central complement component C3 altered in the synergy of HIV infection and preeclampsia?

Objective: In light of complement activation in preeclampsia and HIV infection, this study evaluates the concentration of complement component 3 (C3) in HIV-associated preeclampsia. Method: The study population (n = 76) was equally stratified by pregnancy type (normotensive pregnant and preeclampsia) and by HIV status (HIV positive and HIV negative). The plasma concentration of C3 was determined using a Bioplex immunoassay procedure. Results: We report a significant increase in C3 concentration in the HIV-negative versus the HIV-positive groups (p < 0.05), regardless of pregnancy type. However, based on pregnancy type and irrespective of HIV status, C3 concentration was similar between normotensive versus preeclampsia. Concentration of C3 was significantly increased in the HIV-positive preeclamptic compared HIV-negative preeclamptic groups (p = 0.04). The correlation of C3 with all study groups was non-significant. Conclusion: This study demonstrates that C3 was upregulated in HIV-associated PE compared to HIV- associated normotensive pregnancies. The dysregulation of C3 expression by HIV infection may be attributed to antiretroviral therapy.

Differential expression of the angiotensin receptors (AT1, AT2, and AT4) in the placental bed of HIV-infected preeclamptic women of African ancestry.

The Renin-Angiotensin-Aldosterone System (RAAS) is implicated in the pathophysiology of preeclampsia (PE). There is a paucity of data on uteroplacental angiotensin receptors AT1-2 and 4. We evaluated the immunoexpression of AT1R, AT2R, and AT4R within the placental bed of PE vs. normotensive (N) pregnancies stratified by HIV status. Placental bed (PB) biopsies (n = 180) were obtained from N and PE women. Both groups were stratified by HIV status and gestational age into early-and late onset-PE. Immuno-labeling of AT1R, AT2R, and AT4R was quantified using morphometric image analysis. Immunostaining of PB endothelial cells (EC) and smooth muscle cells of spiral arteries (VSMC) displayed an upregulation of AT1R expression compared to the N group (p < 0.0001). Downregulation of AT2R and AT4R expression was observed in PE vs. N group (p = 0.0042 and p < 0.0001), respectively. AT2R immunoexpression declined between HIV+ve and HIV-ve groups, while AT1R and AT4R displayed an increase. An increase in AT1R expression was noted in the EOPE-ve/+ve and LOPE-ve/+ve compared to N-ve/N+ve. In contrast, AT2R and AT4R expression decreased in EOPE-ve/+ve and LOPE-ve/+ve compared to N-ve/N+ve. We demonstrate a significant downregulation of AT2R and AT4R with a concomitant elevated AT1R immunoexpression within PB of HIV-infected PE women. In addition, a decline in AT2R and AT4R with an increase in AT1R immunoexpression in PE, EOPE, and LOPE vs. normotensive pregnancies, irrespective of HIV status. Thus highlighting differential immunoexpression of uteroplacental RAAS receptors based on pregnancy type, HIV status, and gestational age.

Appraisal of hepatocyte growth factor signal transduction in the duality of HIV associated pre-eclampsia.

INTRODUCTION: Hepatocyte Growth Factor (HGF) is a potent mitogen with a tyrosine kinase receptor (HGFR), which upon binding and activation functions to promote angiogenesis, tumorigenesis, cell growth, cell mortality and morphogenesis via the RAS/MAPK/ ERK, PI3K/ PKB/AKT and JAK/ STAT3 pathways. Both HGF and its receptor, HGFR play an essential role in human placentation and embryonic development during pregnancy. This study determines the concentration of HGF and HGFR in the synergy of HIV infection and pre-eclampsia (PE). MATERIAL AND METHODS: A total sample size of n = 80 (n = 40 pre-eclamptic and n = 40 normotensive) women was used. These were further stratified into HIV-positive and HIV-negative women. Analysis of the growth factors were performed via the Bio-Plex multiplex immunoassay method. RESULTS: The expression of serum HGF, based on pregnancy type irrespective of HIV status, was significantly downregulated in preeclamptic women vs normotensive women (p ≤ 0.005). In contrast HGFR expression was similar between the latter groups (p ≤ 0.4956). Based on HIV status, both HGF and HGFR expression showed no significant difference between HIV- positive and HIV-negative women, regardless of pregnancy type (p = 0.4409; p = 0.8869). There was a significant difference of HGF and HGFR across all study groups (p ≤ 0.0001) with a moderate correlation between HGF and HGFR. CONCLUSION: This study demonstrates a downregulation of HGF expression in preeclampsia compared to normotensive pregnancies irrespective of HIV status. This decline impedes trophoblast cell survival and apoptosis via aberrant signalling pathways that contribute to defective trophoblast invasion in PE. The similarity of HGF and HGFR in HIV positive and negative groups emanates from the immune restorative effect of anti-retroviral usage.

HIV Associated Preeclampsia: A Multifactorial Appraisal.

Introduction: This review explores angiogenesis, vascular dysfunction, the complement system, RAAS, apoptosis and NETosis as potential pathways that are dysregulated during preeclampsia, HIV infection and ART usage. Results: HIV-1 accessory and matrix proteins are protagonists for the elevation of oxidative stress, apoptosis, angiogenesis, and elevation of adhesion markers. Despite the immunodeficiency during HIV-1 infection, HIV-1 exploits our cellular defence arsenal by escaping cell-mediated lysis, yet HIV-1 infectivity is enhanced via C5a release of TNF-α and IL-6. This review demonstrates that PE is an oxidatively stressed microenvironment associated with increased apoptosis and NETosis, but with a decline in angiogenesis. Immune reconstitution in the duality of HIV-1 and PE by protease inhibitors, HAART and nucleoside reverse transcriptase, affect similar cellular pathways that eventuate in loss of endothelial cell integrity and, hence, its dysfunction. Conclusions: HIV-1 infection, preeclampsia and ARTs differentially affect endothelial cell function. In the synergy of both conditions, endothelial dysfunction predominates. This knowledge will help us to understand the effect of HIV infection and ART on immune reconstitution in preeclampsia.

A Narrative Review of the Renin-Angiotensin-Aldosterone System in the Placenta and Placental Bed of HIV Infected Women of African Ancestry with Preeclampsia.

PURPOSE OF REVIEW: Both HIV infection and preeclampsia (PE), a pregnancy-specific disorder of hypertension and multi-system organ involvement, have high prevalence rates especially in low-to-middle-income countries. The immunoexpression of specific renin-angiotensin-aldosterone system (RAAS) receptors in the placenta and placental bed interface may forecast the risk of PE. RECENT FINDINGS: Preeclampsia is a leading risk factor for mortality worldwide and remains a challenge in HIV-infected individuals especially those on antiretroviral therapy (ART). Irregular RAAS stimulation may be linked to the pathophysiology of hypertension in HIV infection and in PE. The AT1 receptor is expressed across all trimesters of pregnancy, within placental tissue, eliciting vasoconstriction. This increased expression is associated with the severity of PE, implying that the increased expression may be involved in the pathogenesis of this pregnancy disorder. The AT2 receptor expression in normotensive pregnancies was shown to be lower as compared to non-pregnant individuals. Furthermore, in the PE placental bed, the AT2 receptor is the predominant receptor subtype and is found in extravillous trophoblast cells where they facilitate vasodilation. However, AT4R in placentae of PE pregnancies are found to be significantly reduced compared to normotensives pregnancies. The data on the role played by the RAAS pathway in pregnancy is conflicting. Investigation into a tissue-based RAAS with emphasis on immune-expression within the placenta and placental bed may help resolve this conundrum.