# Role of NOX4 and redox environment in Autosomal Dominant Polycystic Kidney Disease

> **NIH NIH R56** · MAYO CLINIC ROCHESTER · 2020 · $100,000

## Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder, resulting in
approximately $3.3 billion cost per year to the US health care system. It is characterized by progressive
development and enlargement of bilateral renal cysts leading to renal failure. Early nephron-protective
strategies may alter the course of the disease, but the mechanisms contributing to disease severity and
progression remain to be fully elucidated, limiting the development of new therapies. Furthermore, the follow
up and evaluation of a treatment response in patients represents a major challenge due to the large phenotypic
variability, the natural course of the disease and limitations in currently available biomarkers. It has been
proposed that loss of functional polycystin-1 and polycystin-2 (main ADPKD protein products) result in reduced
intracellular Ca+2, cAMP accumulation and activation of protein kinase A (PKA) signaling. In addition, ADPKD
has been associated with increased renal reactive oxygen species (ROS), mitochondrial abnormalities and
metabolic dysregulations early on the disease, likely influencing disease progression. The connection between
these processes remains unresolved. Intracellular signaling, organelles, and metabolic pathways are
influenced by the redox environment, which is determined by the production and removal of ROS, due to
ROS's ability to activate or deactivate a variety of enzymes and signaling molecules. Our preliminary data in
Pkd1RC/RC mice shows an early upregulation in renal ROS producer NADPH oxidase 4 (NOX4), associated with
mitochondrial abnormalities and metabolic dysregulations that correlates with disease severity and
progression. NOX4 upregulation and metabolic abnormalities were more pronounced in a Pkd1RC/RC model
with constitutive upregulation of PKA, consistent with previous studies in endothelial cells showing upregulation
of NOX4 via cAMP/PKA/CREB-dependent pathway. How NOX4 affects the cellular redox environment and its
influence in mitochondrial function and metabolic pathways, and whether activation of PKA signaling leads to
NOX4 upregulation are not known. Our central hypothesis is that PKA-mediated NOX4 upregulation,
dynamically regulates the cellular redox environment inducing mitochondrial abnormalities and
metabolic dysregulations, and contributes to disease severity and progression. Three specific aims will
be pursued: Aim 1: will determine the impact of NOX4 in cellular redox environment, mitochondria structure
and function and metabolic pathways in ADPKD and the contribution to disease severity and progression. Aim
2: will test whether activation of PKA signaling induces early NOX4 upregulation in ADPKD. Aim 3: will
determine whether urine NOX4, surrogate markers of mitochondria injury and oxidative stress may be useful
real-time biomarkers to assess disease severity and progression in patients with early ADPKD. Successful
studies will have important clinical implications by adv...

## Key facts

- **NIH application ID:** 10253060
- **Project number:** 1R56DK126700-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Maria V Irazabal
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253060

## Citation

> US National Institutes of Health, RePORTER application 10253060, Role of NOX4 and redox environment in Autosomal Dominant Polycystic Kidney Disease (1R56DK126700-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10253060. Licensed CC0.

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