# Nuclease mechanisms in acute kidney injury

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2024 · —

## Abstract

American Veterans are disproportionately affected by kidney-damaging agents during
deployment operations, and failing health and medical countermeasures add long-term health
effects. Studies admit the urgent need to develop novel protective or preventive strategies to
overcome the short therapeutic window for kidney protection. Thus, a therapy based on the
delayed effects of acute kidney injury (AKI) would be clinically relevant because it gives a wider
therapeutic window for intervention. The study of kidney nucleases initiated by our group
several years ago has determined that of nine known endonucleases, DNase I and EndoG are
the most active and mechanistically involved in tubular epithelial cell death during AKI. Our
unexpected finding was that one of the endonucleases, EndoG, that has RNase activity,
induced alternative splicing (AS) of DNase I pre-mRNA, thus inactivating DNase I and mitigating
other DNases’ expression. Our data also showed that EndoG indices AS of other genes.
Therefore, this proposal is focused on EndoG-mediated pathways through its RNase and
DNase activities. We hypothesize that during AKI, EndoG induces tubular epithelial cell death
by fragmenting DNA and causing alternative pre-mRNA splicing of several proteins including
DNase I, while endonuclease inhibitors will mitigate this injury. In Aim 1 we will determine
EndoG RNase-mediated mechanisms in normal kidney and during myoglobinuric AKI. This aim
will determine (a) the protective mechanisms of EndoG against DNase I expression, and (b) the
mechanism of AS mediated by EndoG. Aim 2 will define the role of EndoG DNase activity, the
mechanisms of EndoG and DNase I leakage to the nucleus, and the role of ROS in the
induction of endonucleases during myoglobinuric AKI. Finally, Aim 3 will evaluate the
therapeutic modulation of EndoG for kidney tissue protection and limiting AS in myoglobinuric
and other AKI models. Inhibition of individual endonucleases with the use of our one-of-a-kind
chemical inhibitors will be tested.
 Potential Impact on Veterans Health Care. The results of this study will benefit American
Veterans and the general population by providing critical knowledge of endonuclease-mediated
mechanisms of AKI and their therapeutic targeting. These studies can potentially lead to the
development of new therapeutic tools (endonuclease inhibitors) to prevent or ameliorate
myoglobinuric AKI. Some of them will have strong translational value because they act even if
administered after kidney injury, while others can become future therapeutic options. When
applied to humans, the results of this study may allow for saving human lives, improving the
health of Veterans, and decreasing the number of disabilities in the Veteran population.

## Key facts

- **NIH application ID:** 10925591
- **Project number:** 2I01BX002425-09A1
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** Alexei G Basnakian
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-10-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925591

## Citation

> US National Institutes of Health, RePORTER application 10925591, Nuclease mechanisms in acute kidney injury (2I01BX002425-09A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10925591. Licensed CC0.

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