Date of Award

January 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Advisor

Seema Somji

Abstract

Cisplatin is a widely used chemotherapeutic agent known for its efficacy against various solid tumors, but its clinical utility is limited by dose-dependent nephrotoxicity. The renal proximal tubule, particularly its epithelial cell population, is highly susceptible to cisplatin-induced injury due to its role in solute transport and high metabolic activity. Recent advances suggest that renal progenitor cells play a key role in epithelial repair following nephrotoxic injury; however, the molecular mechanisms underlying their response to cisplatin remain poorly understood.This study investigates the impact of both acute and chronic cisplatin exposure on immortalized human renal progenitor cells (HRTPT, CD24⁺/CD133⁺) using a combination of transcriptomic (RNA sequencing) and proteomic (TMT-labeled mass spectrometry) approaches. Morphological changes and platinum accumulation were evaluated using microscopy and ICP-MS, respectively. RNA-seq data revealed progressive transcriptional reprogramming across passages, marked by the upregulation of DNA damage response, oxidative stress, and apoptosis pathways, alongside suppression of metabolic and transport-related genes. Proteomic analyses supported these findings, highlighting alterations in mitochondrial function and inflammatory signaling. Notably, partial discordance between transcript and protein levels suggested possible post-transcriptional regulation during cisplatin adaptation. The results demonstrate that HRTPT cells exhibit adaptive molecular responses to cisplatin-induced stress, including changes in gene expression, protein regulation, and cellular phenotype. These findings enhance our understanding of renal progenitor cell-mediated repair mechanisms and offer potential targets for therapeutic intervention to mitigate cisplatin nephrotoxicity. This study also validates HRTPT cells as a physiologically relevant in vitro model for studying nephrotoxic injury and regeneration in the human kidney.

Download

Share

COinS