TRIP13-deficient tubular epithelial cells are susceptible to apoptosis following acute kidney injury

Jeffrey D Pressly,Taketsugu Hama,Kevin R Regner,Shannon O’ Brien,Frank Park

doi:10.1038/srep43196

Abstract

Damage to renal tubular epithelial cells by genetic, environmental, or biological insults can initiate complex signaling mechanisms that promote kidney repair and functional recovery. In this study, we demonstrated that thyroid receptor interacting protein 13 (TRIP13) is a critical modulator of tubular epithelial cell repair following ischemia‐reperfusion injury (IRI), a common type of renal stressor. In Trip13Gt/Gthypomorph mice treated with unilateral renal IRI, persistent tubular epithelial cell damage was determined in the IRI-treated kidney throughout the 168 hours of experimental period compared to the contralateral kidneys. The damaged epithelial cells were associated with increased levels of DNA damage (ɣH2AX) and apoptotic markers (p53, cleaved caspase-7, and TUNEL-positive cells). Correspondingly, TRIP13 was found to directly interact with Tetratricopeptide Repeat Domain 5 (TTC5), a p53 co‐factor, and genetic knockdown of TRIP13 in murine inner medullary collecting duct cells in the presence of hydrogen peroxide showed increased activity of p53 at Serine 15. In all, these studies suggest that insufficient TRIP13 increased the susceptibility of damaged tubular epithelial cells to progress towards apoptotic cell death.

Highlights

TRIP13 interacts with kinetochores to ensure that the fidelity of chromosome segregation at the spindle assembly checkpoint during anaphase is maintained[18,20,29,30,31]
Ischemia-reperfusion injury (IRI) is one of the major types of biological stresses imposed upon the kidney, on the outer medullary tubular epithelial cells[1]
ischemia-reperfusion injury (IRI) can results in a modest to severe decrease in viable renal tubules by increasing exposure to oxidative stress and inflammatory cell recruitment, which can lead to DNA damage[1]

Summary

Introduction

TRIP13 interacts with kinetochores to ensure that the fidelity of chromosome segregation at the spindle assembly checkpoint during anaphase is maintained[18,20,29,30,31]. TRIP13 was responsible for efficient DNA repair following ionizing radiation or chemotherapy by promoting nonhomologous end joining (NHEJ), and this resulted in enhanced survival of head and neck tumor cells leading to continued pathological growth[21]. These findings suggest that TRIP13 can function as a key surveillance protein to help assess DNA integrity by providing a mechanism of DNA repair while functioning to maintain spindle assembly during cell division. The present study was designed to investigate the role of TRIP13 in the context of acute renal tubular injury and recovery by determining the expression profile, localization, and biological function of TRIP13 following IRI using normal and hypomorph Trip[13] mice

Methods

Results

Conclusion