# The Kidney, Hypertension, Pregnancy and Inflammation

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $316,438

## Abstract

Preeclamptic (PE) women have elevated circulating cytokines, Natural killer cells, T cells and blood
pressure, however, the pathway linking placental ischemia and immune activation with the hypertension and
IUGR during pregnancy is unknown. One possible mechanism is that chronic inflammation from CD4+THelper 1
cells results in the release of cytokines activating cytolytic NK cells which promotes oxidative stress leading to
IUGR and endothelial dysfunction leading to altered renal hemodynamics and hypertension. We have shown
that reduced uterine perfusion pressure (RUPP) in pregnant rats, a rat model of PE, is an important stimulus
for hypertension and chronic inflammation which is associated with reductions in renal plasma flow, GFR, and
renal excretory function. Our preliminary data indicate the RUPP is associated with an imbalance among the T
regulatory (↓TReg) and T helper 17 cells (↑ THelper 17) and increased activated NK cells and that adoptive transfer
of RUPP THelper 17 cells into normal pregnant rats causes hypertension and IUGR. Our preliminary data
demonstrates that adoptive transfer of TReg from normal pregnant rats into RUPP rats decreased hypertension
and inflammatory cytokines. Importantly we demonstrate that adoptive transfer of CD4+ T cells from PE
women increase blood pressure in NP Nude/Athymic pregnant rats. These studies demonstrate the importance
of these T cell subtypes in pathological pregnancies. We believe the decrease in the TReg cells and increased
TH17 causes prolonged activation of NK cells that attack the placenta leading to IUGR and for prolong
activation of cytokines leading to the production of vasoactive substances, ET-1 and ROS. The central
hypothesis to be tested that placental ischemia induced increases in CD4+THelper 1 cells lead to increases in
TH17 and decreases in TRegs that in turn results in increases in IL-2, IL-17, and IL-15. These cytokines then
stimulate NK cytolytic activity, thereby increasing placental and renal oxidative stress and contributing to
hypertension and IUGR during pregnancy. To test this hypothesis an integrative physiological approach
complemented with molecular, pharmacological immunological, in vitro cell culture and in vivo techniques will
be used to address the following 3 specific aims:
Specific Aim 1. To test the hypothesis that increases in CD4+THelper 1 cells from PE women or in response to
placental ischemia results in NK cell activation leading to placental and renal oxidative stress via perforin-
granzyme mediated cytotoxicity and hypertension during pregnancy
Specific Aim 2. To test the hypothesis that Thelper17 from PE women or in response to placental ischemia cause
NK cell activation via IL-17.
Specific Aim 3. To test the hypothesis that increased IL-2 as a result of decreased CD4+T regulatory cells
increases blood pressure and stimulates NK cells in response to placental ischemia.

## Key facts

- **NIH application ID:** 9949735
- **Project number:** 5R01HD067541-10
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Babbette LaMarca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,438
- **Award type:** 5
- **Project period:** 2011-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949735

## Citation

> US National Institutes of Health, RePORTER application 9949735, The Kidney, Hypertension, Pregnancy and Inflammation (5R01HD067541-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9949735. Licensed CC0.

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