Urolithiasis: Oxalate Interactions With Renal Cells

描述（由申请人提供）：尿石症是一种多因素疾病，不太可能由单一因素导致整个疾病谱。然而，一个重要因素是草酸盐代谢异常。尿草酸盐增加影响结石形成的方式还不完全清楚，这一直是我们研究的重点。我们已经证明，草酸暴露于肾上皮细胞，结果重新启动的DNA合成，改变基因表达和细胞死亡，并促进晶体保留。然而，具体的信号转导途径参与这些不同的影响草酸盐不了解。本研究将评估p38丝裂原活化蛋白激酶（p38 MAPK）和Jun N-末端激酶（JNK）信号转导通路在介导草酸毒性作用和调节细胞对草酸毒性的反应中发挥核心作用的假设。这一假设是由我们的观察，草酸暴露选择性地引起快速和强大的激活p38 MAPK和JNK的轻度激活，但对ERK 1/ERK 2 MAP激酶通路没有影响。此外，草酸盐引起p38 MAPK和JNK途径选择性激活的精确顺序尚不清楚。本研究的目的有三：（1）阐明草酸诱导p38丝裂原活化蛋白激酶（MAPK）和Jun N-末端激酶（JNK）活化的分子机制，（2）探讨p38 MAPK和Jun N-末端激酶在草酸介导这一作用中的作用;和（3）评价体内p38丝裂原活化蛋白激酶和Jun N-末端激酶途径对高尿症的响应。 了解特定的信号传导过程，介导的草酸盐在肾上皮细胞的影响，将有助于我们制定策略，抑制草酸盐的毒性作用，防止晶体滞留和肾结石的形成。

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.