# NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

> **NIH NIH R01** · NEW YORK MEDICAL COLLEGE · 2022 · $410,000

## Abstract

PROJECT ABSTRACT
Recent advances in neonatal medicine have increased the population of low birth weight (LBW) babies that are
incredibly susceptible for development of hypertension, cardiovascular disease and chronic kidney disease for
unknown reasons as they mature through adulthood. Using an undernourished pregnant mouse model to
generate LBW offspring that develop pathologies similar to those in LBW humans, the proposed studies will
investigate the association of vascular and kidney disease in the LBW adult with systems regulated by
oxidative stress. The study will also examine new potential therapeutic strategies that target vascular oxidant-
regulated mechanisms to treat hypertension and renal dysfunction. Our current studies have provided
evidence for NADPH oxidase-4 (NOX4) driven increases in superoxide-mediated endothelial nitric oxide
dysfunction, thiol oxidation-mediated release of HMGB1 (which potentially activates TLR4) and IL-1β promoted
inflammation as potential driving factors in the disease progression that the LBW adult experiences. Studies in
Aim 1 will examine the consequences of LBW in Nox4 deficient mice and in LBW mice treated with agents that
inhibit NOX4, scavenge superoxide (including superoxide in the mitochondrial matrix), stabilize cytosolic
NADPH redox, and promote heme biosynthesis to define their impact on vascular dysfunction, impairment of
renal perfusion and hypertension development. Measurements of a) redox and metabolic indicators or
signaling mechanisms related to these approaches, b) alterations in vascular function, and c) alterations in
tissue mitochondrial respiration and function will be made to help define driving forces in the progression of
vascular and renal dysfunction that is observed. Using mice deficient in TLR4, and animals treated with
inhibitors of HMGB1 release, TLR4 and IL-1β, studies in Aim 2 will focus on defining the role that the redox
sensor HMGB1 has in causing inflammation, vascular rarefaction, renal fibrosis and glomerular hypertrophy
associated with hypertension and kidney disease. Supporting mechanisms for the HMGB1-TLR4 activation
processes will be defined in cells cultured from control and LBW animals. Studies in this aim will examine the
role of TLR4 in the actions of oxidized forms of HMGB1, and the impact of TLR4 activation on endothelial cell
mitochondrial dysfunction and release of IL-1β. The approaches and measurements made in Aim 1 will also be
used to document the impact of the interventions in Aim 2 on relationships between redox regulatory
processes and aspects of disease progression. It is hypothesized that the redox changes in HMGB1 (identified
by mass spectral analyses) can potentially be modulated by the therapies employed in ways that could help
define the HMGB1 redox forms that are the most pathologically active. It is anticipated that the studies
proposed will document and define the driving factors that promote the progression of hypertension,
cardiovascular and...

## Key facts

- **NIH application ID:** 10320920
- **Project number:** 5R01HL151187-03
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** Brian Blake Ratliff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2019-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320920

## Citation

> US National Institutes of Health, RePORTER application 10320920, NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult (5R01HL151187-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10320920. Licensed CC0.

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