DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
Taketsugu Hama, … , Kevin R. Regner, Frank Park
Taketsugu Hama, … , Kevin R. Regner, Frank Park
Published November 22, 2021
Citation Information: JCI Insight. 2021;6(22):e139092. https://doi.org/10.1172/jci.insight.139092.
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Research Article Nephrology

DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity

Abstract

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.

Authors

Taketsugu Hama, Prashanth K.B. Nagesh, Pallabita Chowdhury, Bob M. Moore II, Murali M. Yallapu, Kevin R. Regner, Frank Park

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Figure 5

Inhibition of double-strand break repair promotes tubular epithelial cell damage.

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Inhibition of double-strand break repair promotes tubular epithelial cel...
(A and B) Nanoparticles (50 μg) containing fluorescent ICG dye were injected into mice and monitored 24 hours later using IVIS system in (A) living mice and (B) ex vivo excised organs. (C) Ex vivo organ fluorescence accumulation (n = 3 animals). K, kidney; Lu, lung; Liv, liver; H, heart; Spl, spleen. Data represent mean ± SD. (D–G) Representative histological images from (D) vehicle- or (E and F) cisplatin-treated (15 mg/kg IP) Trip13Stop/Stop (D and E) and Trip13ΔStop (F) mice. (G) Tubular epithelial cell damage was scored as a percentage of total tubules counted. Serum markers of AKI were monitored for (H) creatinine and (I) NGAL after 72 hours following treatment with cisplatin (15 mg/kg IP) and NP-mirin or NP-Ctrl (50 mg/kg IP). (J) γ-H2AX– (Ser139) and (K) PCNA-positive nuclei in kidney sections at 72 hours following cisplatin treatment with and without mirin. NP without mirin (50 mg/kg IP) was used as the control solution. (L) Relative gene expression change following treatment with cisplatin and/or mirin. Each of the respective groups was compared with mouse kidney values obtained from control vehicle-treated Trip13Stop/Stop mice. (G–K) n = 5–7 mice/group; (L) n=4 mice/group. *P < 0.05, **P < 0.01 between all organs (C) or indicated groups (G, I, J, and L) or all groups (C) using 1-way ANOVA with Tukey’s post hoc analysis. Significance for creatinine (H) was determined using Kruskal-Wallis nonparametric test with Dunn’s post hoc analysis. Scale bar: 100 μm. + = administration of cisplatin or mirin; Cre - = Trip13Stop/Stop; Cre + = ΔStop.