| Autor: |
Hama T; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Nagesh PK; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA., Chowdhury P; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Moore BM 2nd; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Yallapu MM; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA., Regner KR; Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Park F; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA. |
| Abstrakt: |
Cisplatin is a commonly used chemotherapeutic agent to treat a wide array of cancers that is frequently associated with toxic injury to the kidney due to oxidative DNA damage and perturbations in cell cycle progression leading to cell death. In this study, we investigated whether thyroid receptor interacting protein 13 (TRIP13) plays a central role in the protection of the tubular epithelia following cisplatin treatment by circumventing DNA damage. Following cisplatin treatment, double-stranded DNA repair pathways were inhibited using selective blockers to proteins involved in either homologous recombination or non-homologous end joining. This led to increased blood markers of acute kidney injury (AKI) (creatinine and neutrophil gelatinase-associated lipocalin), tubular damage, activation of DNA damage marker (γ-H2AX), elevated appearance of G2/M blockade (phosphorylated histone H3 Ser10 and cyclin B1), and apoptosis (cleaved caspase-3). Conditional proximal tubule-expressing Trip13 mice were observed to be virtually protected from the cisplatin nephrotoxicity by restoring most of the pathological phenotypes back toward normal conditions. Our findings suggest that TRIP13 could circumvent DNA damage in the proximal tubules during cisplatin injury and that TRIP13 may constitute a new therapeutic target in protecting the kidney from nephrotoxicants and reduce outcomes leading to AKI. |
