DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity. JCI Insight 2021 Nov 22;6(22)
Date
11/23/2021Pubmed ID
34806647Pubmed Central ID
PMC8663775DOI
10.1172/jci.insight.139092Scopus ID
2-s2.0-85120382452 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Hama T, Nagesh PK, Chowdhury P, Moore BM 2nd, Yallapu MM, Regner KR, Park FAuthor
Kevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ATPases Associated with Diverse Cellular ActivitiesAcute Kidney Injury
Animals
Cell Cycle Proteins
Cisplatin
DNA Damage
DNA Repair
Disease Models, Animal
Humans
Mice
Mice, Transgenic
