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系。尽管如此，一个重要的因素是草酸代谢异常。尿草酸增加影响结石形成的方式尚不完全清楚，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，导致DNA合成的重新启动，基因表达改变和细胞死亡，并促进晶体保留。然而，草酸盐这些不同作用的具体信号转导途径尚不清楚。这些研究将评估p38丝裂原活化蛋白激酶（p38 MAPK）和Jun n-末端激酶（JNK）信号转导途径在介导草酸盐毒性作用和调节草酸盐毒性的细胞反应中发挥核心作用的假设。这一假设是基于我们的观察，草酸盐暴露选择性地引起p38 MAPK的快速和强大的激活和JNK的轻度激活，但对ERK1/ERK2 MAP激酶途径没有影响。此外，草酸盐引起p38 MAPK和JNK通路选择性激活的确切序列尚不清楚。目前的研究有三个目的：(1)阐明草酸诱导p38丝裂原活化蛋白激酶和Jun n-末端激酶途径的分子机制；(2)探讨p38丝裂原活化蛋白激酶途径和Jun n-末端激酶途径在草酸盐介导作用中的作用；(3)评估p38丝裂原活化蛋白激酶和Jun n-末端激酶途径在体内对高草酸尿的反应。了解介导草酸盐在肾上皮细胞中的作用的特定信号传导过程将有助于我们制定抑制草酸盐毒性作用的策略，防止晶体保留和肾结石形成。

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.