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Abstract
Nephrolithiasis is a multi-factorial disease which, in the majority of cases, involves the renal deposition of calcium oxalate. Oxalate is a metabolic end product excreted primarily by the kidney. Previous studies have shown that elevated levels of oxalate are detrimental to the renal epithelial cells; however, oxalate renal epithelial cell interactions are not completely understood. In this study, we utilized an unbiased approach of gene expression profiling using Affymetrix HG_U133_plus2 gene chips to understand the global gene expression changes in human renal epithelial cells [HK-2] after exposure to oxalate. We analyzed the expression of 47,000 transcripts and variants, including 38,500 well characterized human genes, in the HK2 cells after 4 hours and 24 hours of oxalate exposure. Gene expression was compared among replicates as per the Affymetrix statistical program. Gene expression among various groups was compared using various analytical tools, and differentially expressed genes were classified according to the Gene Ontology Functional Category. The results from this study show that oxalate exposure induces significant expression changes in many genes. We show for the first time that oxalate exposure induces as well as shuts off genes differentially. We found 750 up-regulated and 2276 down-regulated genes which have not been reported before. Our results also show that renal cells exposed to oxalate results in the regulation of genes that are associated with specific molecular function, biological processes, and other cellular components. In addition we have identified a set of 20 genes that is differentially regulated by oxalate irrespective of duration of exposure and may be useful in monitoring oxalate nephrotoxicity. Taken together our studies profile global gene expression changes and provide a unique insight into oxalate renal cell interactions and oxalate nephrotoxicity.
Highlights
Oxalate is a metabolic end product that is freely filtered at the glomerulus, undergoes bi-directional transport in the renal tubules, and is excreted primarily by the kidney [1,2,3]
These results reveal that oxalate exposure, in addition to turning on gene expression, is associated with the significant suppression of gene expression in renal epithelial cells
While many previous studies have evaluated the over expression of a few genes in renal epithelial cells in response to oxalate, our results presented here profiled oxalate renal cell interactions in an unbiased fashion using microarray gene expression technology
Summary
Oxalate is a metabolic end product that is freely filtered at the glomerulus, undergoes bi-directional transport in the renal tubules, and is excreted primarily by the kidney [1,2,3]. While very high levels of urinary oxalate are observed only in subjects with primary hyperoxaluria, a majority of idiopathic kidney stone patients only show a mild elevation in urinary oxalate [5,6,7,8,9] In addition several other conditions associated with oxalate deposits are: renal cysts in acquired renal cystic disease [7], proliferating cells in the kidney [8], hyperplasic thyroid glands [9], and benign neoplasm of the breast [10,11] These considerations suggest that the pathological deposition of calcium oxalate is more complex than a simple physical precipitation of calcium oxalate crystals. Over the past two decades, studies [13,14,15,16,17,18,19,20,21,22,23] have demonstrated that oxalate interactions with doi:10.1371/journal.pone.0043886.g001
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