Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Siskind, Leah J

Committee Member

Beverly, Levi J

Committee Member

Mitchell, Robert A

Committee Member

Yaddanapudi, Kavitha

Committee Member

Clark, Geoffrey J

Author's Keywords

Onconephrology; kidney; cancer; macrophages; nephrology; chemotherapy

Abstract

Cisplatin remains a mainstay in the treatment of solid tumors, yet its therapeutic efficacy is frequently compromised by dose-limiting nephrotoxicity. Approximately 30% of patients receiving cisplatin develop acute kidney injury (AKI), which increases the risk of chronic kidney disease (CKD), a leading cause of morbidity and mortality. Despite extensive preclinical efforts, no FDA-approved therapy currently exists to prevent or treat cisplatin-induced nephrotoxicity (CIN). This in part is due to the reliance of preclinical studies on non-cancer animal models that fail to capture the complex physiological alterations associated with malignancy. To address this limitation, we developed a clinically relevant model in which mice bearing KrasG12D Trp53KO lung tumor receive repeated low-dose cisplatin (RLDC). This model confirmed that cancer alone is sufficient to induce renal dysfunction and exacerbate CIN, supporting the existence of cancer–kidney crosstalk. Further investigation revealed that this pathological interaction extends to specific distant-organ malignancies, highlighting a broader relevance of cancer-driven nephrotoxicity. Among solid tumors, lung cancer patients exhibit a notably high incidence of AKI, prompting an investigation into the unique pathophysiological interactions rendering the kidney susceptible to nephrotoxicity. Our histological and functional assessments revealed that lung cancer induces renal injury, persistent inflammation, EMT activation, and progressive fibrosis, significantly impairing renal dysfunction. These alterations correlated temporally and spatially with an accumulation of resident and infiltrating macrophages in the kidney, implicating them as potential mediators of cancer-induced nephrotoxicity. To test this hypothesis, we selectively targeted macrophage populations using liposome-encapsulated clodronate to deplete resident macrophages or CCR2 deficiency to deplete monocyte-derived macrophage recruitment. Each strategy independently provided significant protection against proximal tubular injury, as evidenced by decreased KIM-1 expression and preservation of the proximal tubular brush border membrane. Moreover, it reduced the production of extracellular matrix components and significantly attenuated fibrosis.Together, these findings propose macrophages are potential mediators of cancer-induced nephrotoxicity and highlight the importance of dissecting the temporal and phenotypic heterogeneity of the populations involved in cancer–kidney crosstalk. A deeper understanding of these immune dynamics may guide the development of precision therapies that selectively target pathogenic macrophage subsets while preserving immune homeostasis and competence.

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