DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
Taketsugu Hama, Prashanth K.B. Nagesh, Pallabita Chowdhury, Bob M. Moore II, Murali M. Yallapu, Kevin R. Regner, Frank Park
Taketsugu Hama, Prashanth K.B. Nagesh, Pallabita Chowdhury, Bob M. Moore II, Murali M. Yallapu, Kevin R. Regner, Frank Park
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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 4

Constitutive TRIP13 overexpression reduces apoptotic signaling and regulates intracellular signaling pathways.

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Constitutive TRIP13 overexpression reduces apoptotic signaling and regul...
(A–E) Representative images are shown for p–histone H3 (Ser10) in kidney sections obtained from vehicle- and cisplatin-treated Trip13Stop/Stop (A and B) and Trip13ΔStop (C and D) mice after day 3. Arrowheads are pointing at individual or clusters of stained nuclei. (E) A negative control (no primary antibody) section was used from a cisplatin-treated Trip13Stop/Stop mouse. (F) Graphical analysis showing quantitative numbers of nuclei positive for p–histone H3 (Ser10) in each image (3–4 images were counted per kidney section in each mouse). (G) Cyclin B1 bands were shown following Western blot analysis using kidney lysates isolated from Trip13Stop/Stop and Trip13ΔStop mice treated with either vehicle or cisplatin (15 mg/kg IP) after 72 hours. (H) Cleaved caspase-3–positive cells were counted relative to the total number of nuclei. — = vehicle; + = cisplatin (15 mg/kg IP). *P < 0.01 between all groups using 1-way ANOVA with a Tukey’s post hoc analysis. Scale bar: 100 μm (A–D), 200 μm (E). n = 4–8 animals/group.