# Innate Immune Mediated Changes in Renal Function to Cause Hypertension in Females with Autoimmune Disease

> **NIH NIH U54** · AUGUSTA UNIVERSITY · 2024 · $312,598

## Abstract

Primary hypertension is linked with immunological changes, including autoantibody production, that are
consistent with autoimmune underpinnings of hypertension. The innate immune response also has a central role
in the development of autoimmunity; however, the mechanistic contributions of innate immunity to autoimmune
associated hypertension have not been studied. This proposal will examine a novel innate immune feedforward
mechanism that promotes hypertension during systemic lupus erythematosus (SLE), a disorder that
predominantly affects young women, thus significantly advancing the field towards a better understand of
immune mediated hypertension. We previously showed that an experimental female mouse model of human
SLE exhibits impaired renal vascular function and sodium handling, renal oxidative stress, and hypertension that
is ameliorated by antioxidants. Despite this, little is understood about the cellular sources of reactive oxygen
species or the intracellular pathways that drive changes in renal function during SLE associated hypertension.
The innate immune response has an important role in causing tissue damage during SLE. This proposal will
test the central hypothesis that during SLE there is a feedforward mechanism driving the generation of renal
ROS, leading to impaired renal vascular function and increased tubular sodium reabsorption. This cycle involves
the presence of NETs that increase cell stress signals, including HMGB1, TLR4 mediated mitochondrial
dysfunction, and the production of ROS. Mitochondrial ROS activate the NLRP3 inflammasome, which
perpetuates the cycle by promoting further generation of NETs to induce additional cell stress. This will be tested
in three aims (1) During SLE, NETs promote hypertension by increasing renal ROS that causes impaired renal
vascular and tubular function. (2) During SLE, cell stress proteins (HMGB1) increase mitochondrial ROS
generation leading to NLRP3 inflammasome activation and further NET production through a TLR4 mediated
mechanism. (3) A large data cohort (approximately 32,000) from men and women with SLE will be examined for
relationships between clinical markers of inflammation, immunotherapies, and blood pressure. The proposal
uses widely established models of SLE, an innovative genetic model, state-of-the-art physiological,
pharmacological, and immunological methods, along with a national data base of human clinical data to
rigorously test these aims.

## Key facts

- **NIH application ID:** 10918132
- **Project number:** 5U54HL169191-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** MICHAEL RYAN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,598
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918132

## Citation

> US National Institutes of Health, RePORTER application 10918132, Innate Immune Mediated Changes in Renal Function to Cause Hypertension in Females with Autoimmune Disease (5U54HL169191-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10918132. Licensed CC0.

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