# Targeting Pathogenic Endothelial Dysfunction in Lupus Nephritis

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

Systemic lupus erythematosus (SLE) is an immune complex-mediated disease in which clinical disease
manifests after an innate immune response. Endothelial cells (EC) are conditional effector cells activated by
inflammatory stimuli to produce intracellular reactive oxygen species (ROS) and signal for influx of inflammatory
cells into tissue. We have published that endothelial nitric oxide synthase (eNOS) modulates inflammation in
lupus nephritis (LN) and that uncoupling of EC eNOS (which reduces production of anti-inflammatory nitric oxide
(NO) and increases production of pro-inflammatory ROS) is a potential therapeutic target in SLE. We hypothesize
that sepiapterin, a compound that couples eNOS, will improve LN outcomes and vascular function in murine LN
and work by modulating the PI3Kinase/Akt pathway to reduce expression of inflammation and fibrosis genes in
mice and in cultured glomerular endothelial cells. We further hypothesize that the proposed approach may have
off target effects, particularly in T cells, monocyte/macrophages, and podocytes. To address this overarching
hypothesis, the following specific aims are proposed: Specific Aim 1) Determine the effect of sepiapterin in
murine LN on clinical and histologic LN outcomes, large vessel endothelial function, and
pharmacodynamic markers of treatment response. We hypothesize that sepiapterin will improve LN
outcomes and vascular function in murine LN. To determine the effect of and optimal therapeutic indication for
ECD targeted therapy, we will use the NZM2410 model of spontaneous LN and compare groups with and without
sepiapterin treatment to determine effect on three different endpoints. 1) preventing/prolonging LN onset with
sepiapterin monotherapy, 2) in mycophenolate-treated mice, improving/hastening induction of remission with
sepiapterin as an adjunctive therapy, and 3) after inducing remission, prolonging/preventing LN flare with
sepiapterin monotherapy after mycophenolate withdrawal. LN clinical and histologic parameters and large vessel
endothelial function will be the primary endpoints. Biomarkers of systemic oxidative stress will serve as
exploratory pharmacodynamic indicators. Specific Aim 2. Determine differential gene expression and
phosphokinase signaling events, with a focus on the PI3K/Akt pathway, induced in human glomerular
endothelial cells (HRGECs) by LN serum and modulated by sepiapterin. Based on our published and
preliminary studies, we hypothesize that inflammatory gene expression and PDGF receptor/PI3K/Akt/FoxO1
signaling induced by LN flare serum can be modulated by sepiapterin in HRGECs. Knowledge of pathways
activated by LN flare serum that both initiate redox-regulated pathways and that can be modulated by restoring
coupling to eNOS will be important for rational development of therapies to target ECD in LN. We will culture
HRGECs with serum from SLE patients with active nephritis or a cytokine mix and perturb signaling through the
PDGFR, PI3K, and Akt to dete...

## Key facts

- **NIH application ID:** 10487863
- **Project number:** 2I01CX001248-05A2
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** JAMES C OATES
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487863

## Citation

> US National Institutes of Health, RePORTER application 10487863, Targeting Pathogenic Endothelial Dysfunction in Lupus Nephritis (2I01CX001248-05A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10487863. Licensed CC0.

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