OXLATE-INDUCED CHANGES IN GENE EXPRESSION IN HUMAN RENAL EPITHELIAL CELLS: IDENTIFICATION OF GENES INDUCED BY OXALATE.

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Kidney stones affect about 10% of the US population and have an economic impact of 2 to 4 billion US$ anually. The majority (≈80%) of kidney stones are composed of calcium oxalate crystals. Increased urinary oxalate is an established risk factor for nephrolithiasis. Our laboratory was the first to demonstrate that oxalate is nephrotoxic, and oxalate interactions with the renal ells result in a plethora of changes, including cell growth, death, and altered gene expression. Recently, we evaluated oxalate-induced global changes in gene expression in the renal epithelial (HK2) cells by DNA microarray chip that represented 11 independent replicate probe sets for each message. These studies identified several genes whose expression was either up- or down-regulated by oxalate. In the present study, the most strongly up- and down-regulated genes were confirmed using polymerase chain reaction (PCR) in new experiments, where renal epithelial cells (HK2) were exposed to oxalate. We also extended our studies to define time course (1-24 h) of gene expression changes upon oxalate exposure. Results of our current studies confirmed that oxalate-induced time dependent expression of the beta-adrenergic receptor, beta subunit of the IL-2 receptor, and the transcript of a protein whose function is currently unknown. These exciting observations suggest that oxalate may regulate its actions by turning on additional (previously unknown) intracellular pathways that may be involved in stone pathogenesis. Additional studies into these pathways may provide the key to unlocking a biochemical target in stone disease and are currently under way in our laboratory.