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 i n 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.
Deployment operations and civilian disasters are commonly associated with skeletal muscle trauma and degradation (rhabdomyolysis) that causes acute renal injury (AKI). The latter is a life-threatening disease that requires hemodialysis or kidney transplantation. Our studies showed that kidney has a way of protecting itself by interplay of two enzymes, one of which, DNase I, is responsible for the injury, while another, EndoG, provides protection of kidney cells by inactivating DNase I. Currently, there are no pharmacologically-meaningful inhibitors for DNase I or other therapies based on inactivation of these enzymes. Therefore, we propose several new methods to inactivate DNase I for kidney protection in mice using the native mechanism as well as new chemical inhibitors. This study will likely result in new therapies, and may eventually allow saving human lives, improving the health of veterans, and decreasing the number of disabilities in the veteran population.
| Fahmi, Tariq; Branch, La Donna; Nima, Zeid A et al. (2017) Mechanism of graphene-induced cytotoxicity: Role of endonucleases. J Appl Toxicol 37:1325-1332 |
| Fil, Daniel; DeLoach, Abigail; Yadav, Shilpi et al. (2017) Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet 26:686-701 |
| Nedosekin, Dmitry A; Fahmi, Tariq; Nima, Zeid A et al. (2017) Photoacoustic in vitro flow cytometry for nanomaterial research. Photoacoustics 6:16-25 |
| Rogers, Lora J; Basnakian, Alexei G; Orloff, Mohammed S et al. (2016) 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer. Nutr Metab (Lond) 13:54 |
| Zhdanov, Dmitry D; Fahmi, Tariq; Wang, Xiaoying et al. (2015) Regulation of Apoptotic Endonucleases by EndoG. DNA Cell Biol 34:316-26 |
| Barreto-Torres, Giselle; Hernandez, Jessica Soto; Jang, Sehwan et al. (2015) The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPAR?-cyclophilin D interaction in cardiomyocytes. Am J Physiol Heart Circ Physiol 308:H749-58 |
| Jang, Dae Song; Penthala, Narsimha R; Apostolov, Eugene O et al. (2015) Novel high-throughput deoxyribonuclease 1 assay. J Biomol Screen 20:202-11 |
| Shah, Sudhir V; Shukla, Ashutosh M; Bose, Chhanda et al. (2015) Recent advances in understanding the pathogenesis of atherosclerosis in CKD patients. J Ren Nutr 25:205-8 |
| Jang, Dae Song; Penthala, Narsimha R; Apostolov, Eugene O et al. (2015) Novel cytoprotective inhibitors for apoptotic endonuclease G. DNA Cell Biol 34:92-100 |
| Mehta, Jawahar L; Basnakian, Alexei G (2014) Interaction of carbamylated LDL with LOX-1 in the induction of endothelial dysfunction and atherosclerosis. Eur Heart J 35:2996-7 |
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