# Compartment-specific manipulation of NAD+ to mitigate post-injury kidney disease.

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $437,973

## Abstract

PROJECT SUMMARY
Nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH, play crucial roles in maintaining tissue
homeostasis. We now know that NAD+ and NADH concentrations differ in different parts of the cell by orders of
magnitude. Nevertheless, how these distinct cellular pools of NAD+/NADH enable compartment specific
metabolic and regulatory functions, ensuring coordination of various cellular processes remains elusive.
NAD+/NADH compartmentalization is particularly important for the kidneys, in which tubule cells perform the
high-energy demanding task of reclaiming solutes filtered from the bloodstream and eliminating waste products
through urine. In acute kidney injury (AKI), a common condition in elderly patients, substantial decreases in the
levels of NAD+ impair energy generation in tubular epithelial cells leading to critical loss of cellular and organismal
homeostasis. Patients who survive AKI frequently develop chronic kidney disease (CKD), a condition
characterized by kidney fibrosis and inflammation leading to deleterious systemic effects. We and others have
shown that NAD+ boosting by cytoprotective approaches protects the kidney tubules against ischemia and other
insults. Furthermore, several experimental studies have demonstrated protective role for NAD+ precursor
supplementation against aging and AKI but the underlying mechanisms remain elusive. In particular, while the
cellular NAD+/NADH ratio is critical for energy metabolism, the extent to which it reflects versus drives metabolic
physiology in vivo is poorly understood. To successfully translate NAD-based therapeutics in humans, it is
essential to understand the molecular mechanisms by which this metabolite regulates kidney health. To this end,
recent technological advances that allow genetic manipulation of NAD+ in different cellular compartments, have
uncovered an exciting potential for revealing the multi-faceted effects of this fascinating molecule. The goal of
this proposal is to identify novel mechanisms by which directly increasing the NAD+/NADH promotes kidney
health in the context of injury and aging. To this end, we propose in vivo expression of Lactobacillus brevis
(Lb)NOX, a bacterial water forming NADH oxidase, in the cytosol or mitochondrial of kidney tubular cells. Two
specific aims are proposed. Aim 1 will determine how boosting mitochondrial NAD+/NADH ratio in tubular
epithelial cells regulates kidney health following ischemic kidney injury. Aim 2 will define the role of boosting
cytosolic NAD+/NADH in tubular epithelial cells as a regulator of kidney health following ischemic kidney injury.
Completion of this project will generate exciting new insights in kidney biology and enable the development of
urgently needed novel therapeutics that protect kidney health.

## Key facts

- **NIH application ID:** 11055784
- **Project number:** 1R21AG086806-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Pinelopi P. Kapitsinou
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,973
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11055784

## Citation

> US National Institutes of Health, RePORTER application 11055784, Compartment-specific manipulation of NAD+ to mitigate post-injury kidney disease. (1R21AG086806-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11055784. Licensed CC0.

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