# Neuroimmune Regulation of Acute Kidney Injury

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $491,768

## Abstract

Advances in combating acute kidney injury (AKI) require novel and innovative approaches to understanding the
pathogenesis of AKI. AKI leads to death and in some cases progression to ESRD. There are no FDA approved
drugs for the treatment of AKI. An important area of therapeutics - neuroimmunomodulation of disease - is based
upon the interaction between the immune system and the nervous system to defend against injury induced by
inflammation. Our current proposal is based on the observation that vagus nerve stimulation (VNS) activates the
inflammatory reflex pathway, a neuro-immune circuit that is critical in maintaining immunological homeostasis.
Vagal afferent fibers that innervate the kidney are hypothesized to immediately transmit neural impulses to C1
neurons in the lower brainstem that then send efferent signals that terminate on the spleen and other organs to
block inflammation. Recent advances in neuroscience provide refined tools that will permit disentanglement of
neuronal processes that control inflammation and AKI and provide the foundation for therapeutics. Aim 1 will
test the hypothesis that selective afferent and efferent VNS mediate kidney protection by distinct neuronal
pathways. Aim 2 will begin unraveling the central circuitry that mediates the protective anti-inflammatory reflexes
elicited by afferent VNS by testing whether C1 neurons are the central node linking the afferent and efferent
limbs of the inflammatory reflex pathway. The role of C1 neurons, a group of lower brainstem
catecholaminergic/glutamatergic neurons, in the inflammatory reflex pathway and protection from AKI will be the
main focus of our studies in this aim. C1 neurons regulate both sympathetic and parasympathetic efferents, and
we have previously showed that stimulating C1 neurons also protects mice against AKI. Aim 3 will focus on the
effector mechanism of efferent VNS. Here we hypothesize that efferent VNS activates α7nAChR expressed on
IgM-anti-leukocyte auto-antibody (ALA)-producing B1 lymphocytes, which are critical to block inflammation and
AKI. Lastly, we will obtain plasma samples from a completed study of 24 human subjects exposed to VNS to
determine if VNS (suppresses proinflammatory cytokines - focus of the original study) increases plasma levels
of IgM-ALA (focus of the current study). The proposed studies will be conducted using optogenetics and
pharmacogenetics because these approaches offer unprecedented capability to define specific neural circuits
that control immunity and inflammation. These studies leverage a multidisciplinary team consisting of
nephrologists, neuroscientists and immunologists that seek to define a road map of the underlying inflammatory
reflex pathway that protects kidneys from IRI. Attaining genetic and molecular understanding that underlies the
diversity of the vagus nerve pathways controlling inflammation is imperative for the future of precision
bioelectronic medicine.

## Key facts

- **NIH application ID:** 10020389
- **Project number:** 5R01DK123248-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mark Douglas Okusa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,768
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020389

## Citation

> US National Institutes of Health, RePORTER application 10020389, Neuroimmune Regulation of Acute Kidney Injury (5R01DK123248-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020389. Licensed CC0.

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