# Renal mechanisms of hypertension in autoimmune disease

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

The prevalence of hypertension is markedly increased in patients with autoimmune disorders, and growing
evidence links primary hypertension to immunological changes associated with autoimmunity including the
production of autoantibodies (IgG). The underlying mechanisms by which autoimmunity contributes to the
prevalent hypertension in the general population and U.S. active duty military and veterans remains poorly
understood. This proposal will directly advance our understanding of hypertension during autoimmunity, thus
narrowing a knowledge gap that will ultimately lead to improved treatment of hypertension not only for U.S.
military veterans, but also for patients with primary hypertension. We previously established that 1) an
experimental mouse model closely mimics human SLE including the prevalent hypertension with significant
renal immune cell infiltration; 2) mice with SLE have impaired renal vascular function and renal sodium
handling as an underlying factor in development of hypertension; 3) renal production of reactive oxygen
species is increased, and treatment with general antioxidants attenuates the hypertension in mice with SLE; 4)
immunosuppressive and anti-inflammatory treatments protect against the development of hypertension during
SLE in association with reduced renal oxidative stress; and 5) circulating IgG, a critical pathogenic mechanism
of autoimmune diseases, directly contribute to the hypertension in mice with SLE. Taken together, these
studies strongly suggest that immune mediated increases in renal oxidative stress is a fundamental
mechanism leading to the prevalent hypertension during autoimmunity. Despite this evidence, surprisingly little
is understood about the cellular sources of reactive oxygen species in the kidneys, or the intracellular
mechanisms that increase renal oxidative stress during SLE. In a preliminary study, we show that renal
neutrophils are increased in mice with SLE and that these same mice make IgG to myeloperoxidase, an
enzyme essential for the neutrophil oxidative burst and associated with neutrophil extracellular traps (NETs)
that are pathogenically linked to autoimmune disease in humans. In addition, we identified IgG raised against
mitochondrial antigens, and have preliminary data showing that mitochondrial respiration is impaired, along
with increased production of mitochondrial reactive oxygen species. Taken together, these data suggest a
central role for IgG, neutrophils and mitochondrial dysfunction in the pathogenesis of autoimmune mediated
hypertension. This proposal will examine how NETs and IgG act at the cellular level to cause mitochondrial
dysfunction in a feed forward mechanism. We propose that this feed forward mechanism is propagated by IgG
mediated activation of FcγR, and the subsequent activation of the NLRP3 inflammasome. Based on our
preliminary and published data, our central hypothesis is that during SLE, NETs initiate mitochondrial damage
in the kidney that leads to the pro...

## Key facts

- **NIH application ID:** 10436800
- **Project number:** 5I01BX002604-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** MICHAEL RYAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436800

## Citation

> US National Institutes of Health, RePORTER application 10436800, Renal mechanisms of hypertension in autoimmune disease (5I01BX002604-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436800. Licensed CC0.

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