Roles of DNA damage in renal tubular epithelial cells injury

Abstract

The prevalence of renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing worldwide. However, the pathogenesis of most renal diseases is still unclear and effective treatments are still lacking. DNA damage and the related DNA damage response (DDR) have been confirmed as common pathogenesis of acute kidney injury and chronic kidney disease. Reactive oxygen species (ROS) induced DNA damage is one of the most common types of DNA damage involved in the pathogenesis of acute kidney injury and chronic kidney disease. In recent years, several developments have been made in the field of DNA damage. Herein, we review the roles and developments of DNA damage and DNA damage response in renal tubular epithelial cell injury in acute kidney injury and chronic kidney disease. In this review, we conclude that focusing on DNA damage and DNA damage response may provide valuable diagnostic biomarkers and treatment strategies for renal diseases including acute kidney injury and chronic kidney disease.

Keywords: AKI (acute kidney injury); CKD—chronic kidney disease; DDR; DNA damage; DNA repair; tubular epithelial cells.

FIGURE 1

Sources and types of DNA damage and DNA repair. Both exogenous factors and endogenous factors can cause DNA damage. Exogenous factors contain ultraviolet radiation, ionizing radiation, human-made mutageniccompounds, environmental stressors, and other natural toxins. Endogenous biological activities can damage DNA in many ways, including oxidative DNA Damage, DNA methylation, hydrolysis of bases, and depurination/depyrimidination. The common types of DNA damage include base mismatches (insertions/deletions), ssDNA breaks (8-Oxoguanine), dsDNA breaks (Interstrand crosslinks), and DNA adducts (intrastrand crosslinks). Their corresponding DNA repair methods are mismatch repair (MMR), base-excision repair (BER)/non-homologous end-joining (NHEJ), and transcription-coupled/global genome repair. When different types of DNA lesions activate DNA-damage response proteins, DNA repair begins. The signaling pathways that these proteins then activate include those for DNA repair, cell cycle arrest, apoptosis, and senescence. Uncontrolled cell proliferation (cancers), cell death, and genome instability result from dysregulation of DNA damage response and repair, and several of these proteins offer potential therapeutic targets.