Urolithiasis: Oxalate Interactions With Renal Cells

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DESCRIPTION (provided by applicant): Urolithiasis is a multi-factorial disease and it is unlikely that a single factor will be responsible for the entire spectrum of this disorder. Nonetheless, one important factor is an abnormality in the oxalate metabolism. The manner by which increase in urinary oxalate influences stone formation is not completely understood and has been the focus of our investigation. We have demonstrated that oxalate exposure to renal epithelial cells, results in re-initiation of the DNA synthesis, altered gene expression and cell death, and- promotes crystal retention. However, the specific signal transduction pathways involved in these diverse effects of oxalate are not understood. The proposed studies will evaluate the hypothesis that p38 Mitogen-activated Protein kinase (p38 MAPK) and Jun N-terminal kinase (JNK) signal transduction pathways play a central role in mediating the toxic effects of oxalate and in modulating the cellular responses to oxalate toxicity. This hypothesis is driven by our observations that oxalate exposure selectively caused a rapid and robust activation of p38 MAPK and a mild activation of JNK but had no effect on ERK1/ERK2 MAP kinase pathway. Moreover, the precise sequence/s through which oxalate causes selective activation of p38 MAPK and JNK pathways is/are not understood. The present studies have three objectives: (1) to elucidate the molecular mechanisms involved in oxalate induced activation of p38 Mitogen-activated Protein kinase and Jun N-terminal kinase pathways; (2) to investigate the roles played by p38 Mitogen-activated Protein kinase pathway and Jun N-terminal kinase pathway in mediating the effects of oxalate; and (3) to evaluate the activation of p38 Mitogen-activated Protein kinase and Jun N-terminal kinase pathways, in vivo, in response to hyperoxaluria. Understanding the specific signaling processes that mediate the effects of oxalate in renal epithelial cells will help us develop strategies to inhibit the toxic effects of oxalate and prevent crystal retention and renal stone formation.