Date of Award

January 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Advisor

Scott Garrett

Abstract

Studies on populations exposed to inorganic arsenic (iAs) have shown an association between this particular exposure and the development of chronic kidney disease (CKD) and renal cell carcinoma (RCC). However, there are few studies addressing how acute exposure of the human kidney to iAs might lead to long-term alterations that might lead to CKD or RCC. This study’s hypothesis is that renal exposure to iAs might alter the renal cells responsible for the repair and regeneration of nephrons damaged by iAs exposure or other renal toxicants. The kidney possesses a minority epithelial cell population that co-express PROM1 and CD24 that are believed to be involved in renal epithelial cell repair. The cells, termed progenitor cells, may arise from an existing cell population within the kidney or arise from dedifferentiated damage tubule cells. The HRTPT cell line is an immortalized human renal cell line that co-expresses PROM1 and CD24 with properties expected of a cell capable of renal nephron repair and regeneration. Arsenic, in the form of inorganic arsenite, is toxic to the kidney and can cause acute kidney injury, manifesting as destruction of proximal tubule cells. Nephron repair is possible through the proliferation of resident tubular progenitor cells expressing CD133 and CD24 surface markers. This study simulated regenerative repair in the continued presence of i-As (III) using a cell culture model of a renal progenitor cell line expressing CD133 (PROM1) and CD24. Continued exposure and subculturing of progenitor cells to i-As (III) led to a reduction in the expression of PROM1 and CD24 as well as a decrease in the ability to differentiate into tubule-like structures. Cessation of i-As (III) and recovery up to 3 passages resulted in continued repression of PROM1 and reduced ability to differentiate. Chronically exposed cells exhibited an ability to form colonies in soft agar suggesting neoplastic transformation. Chronically exposed cells also exhibited an induction of CD44, a cell surface marker commonly found in renal cell carcinoma as well as in tubular repair in chronic renal injury such as in chronic kidney disease. These results demonstrate potential adverse outcomes of renal progenitor cells chronically exposed to a nephrotoxicant as well as in environmental exposure to arsenic.

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