# DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2020 · —

## Abstract

The United States Armed Forces are routinely exposed to hazardous weapons, pathogens,
environmental toxins and, later, medical countermeasures with long-term health effects. The
kidney is affected by many toxins metabolized in the body that it excretes, including products of
rhabdomyolysis (skeletal muscle degradation), hemolysis, drugs, and exogenous toxins. Many
of these compounds cause acute kidney injury (AKI) by producing reactive oxygen species
(ROS), which activate apoptotic endonucleases. The resulting acute kidney failure (AKF) is a
life-threatening condition that requires hemodialysis or kidney transplantation. This proposal is a
continuation of the previous research funded by a VA Merit Review grant. The specific aims in
the previous project have been accomplished and the new goals are logical extensions of these
aims. The results from the previous study show the importance of two DNA-degrading enzymes,
cytoplasmic deoxyribonuclease I (DNase I) and mitochondrial endonuclease G (EndoG) in
mediating myoglobinuric AKI induced by rhabdomyolysis. Our data indicate that the two
enzymes are linked in a sophisticated network. To sort out the mechanisms of endonuclease
regulation, and to develop an anti-endonuclease drugs for the future, we have identified several
non-toxic endonuclease inhibitors with promising pharmaceutical potentials. We hypothesize
that during myoglobinuric AKI, (a) endonucleases led by DNase I act as a network in which
individual enzymes can induce each other through DNA breaks; (b) EndoG can inactivate
DNase I by alternative splicing (AS) through its RNase activity; and (c) anti-endonuclease
therapy or prevention of AKI should be aimed at both individual endonucleases and the entire
network. Our specific objectives are as follows. In Aim 1, we will delineate DNase I-mediated
mechanisms of regulation of endonucleases during myoglobinuric AKI. In Aim 2, we plan to
define EndoG-mediated mechanisms of regulation of endonucleases during myoglobinuric AKI.
Aim 3 will evaluate therapeutic modulation of endonucleases for kidney tissue protection, and
assess the generality of the observed regulatory mechanisms in other AKI models.
 Potential Impact on Veterans Health Care. Successful completion of these studies can
potentially lead to the development of new therapeutic tools 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 therapeutic options of the future.
When applied to humans, the results of this study may allow saving human lives, improving the
health of veterans, and decreasing the number of disabilities in the veteran population.

## Key facts

- **NIH application ID:** 9784465
- **Project number:** 2I01BX002425-05A1
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** Alexei G Basnakian
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9784465

## Citation

> US National Institutes of Health, RePORTER application 9784465, DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis (2I01BX002425-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9784465. Licensed CC0.

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