Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Siskind, Leah

Committee Co-Chair (if applicable)

Beverly, Levi

Committee Member

Beverly, Levi

Committee Member

Hill, Bradford

Committee Member

Jones, Steven

Committee Member

Clark, Geoffrey

Author's Keywords

AKI; CKD; Cisplatin; Onconephrology


Cancer patients represent a unique patient population with increased susceptibility to kidney disease. Drug-induced acute kidney injury (AKI) in cancer patients is a common problem. Cisplatin is a highly effective treatment used in many solid organ cancers. However, cisplatin causes AKI in 30% of patients, increasing the risk of chronic kidney disease (CKD) development. The kidneys maintain homeostasis of the body’s extracellular fluids and removing waste products. The kidneys filter nearly 170 liters of fluid a day and must reabsorb over 99% of the filtrate. The reabsorption occurs in tubule cells throughout the nephron, which are highly enriched in mitochondria to complete this task. One mechanism by which cisplatin induces nephrotoxicity is by reducing mitochondrial content and biogenesis leading to loss of kidney function, kidney injury, inflammation, and development of fibrosis. Reduced kidney mitochondrial mass and respiration also impairs the tissue repair process. Historically, most preclinical cisplatin toxicity studies have been completed in mice without cancer. We believe the physiology of cancer patients is not adequately represented in these non-cancerous murine models. In this study we used multiple mouse models of lung cancer in combination with repeated low dose cisplatin (RLDC) regimen to determine if cancer alters the nephrotoxicity of cisplatin. Additionally, we pharmacologically induced mitochondrial biogenesis to increase kidney mitochondrial content to determine if this pathway will protect from cisplatin-induced nephrotoxicity. Our results show that lung cancer combined with cisplatin enhances the nephrotoxicity of cisplatin. Additionally, cancer alone without cisplatin reduced renal function, increased fibrosis, reduced mitochondrial content, and reduced PGC-1α of kidney cortices. Stimulating mitochondrial biogenesis increased kidney mitochondrial content and reduced loss of kidney function, kidney injury, inflammation, and development of fibrosis from RLDC in mice without cancer. However, these effects are nullified when the experiment was repeated in mice with subcutaneous lung cancer. Previous clinical trials on nephroprotective agents have failed, and we propose that poorly representative mouse models may be responsible for misleading preclinical research. Our development of clinically relevant models of cisplatin-induced nephrotoxicity provides a foundation for developing nephron-protective agents that can be used as an adjunctive therapy for cancer patients taking cisplatin.