Jonassen Julie A, Cao Lu-Cheng, Honeyman Thomas, Scheid Cheryl R
Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Crit Rev Eukaryot Gene Expr. 2003;13(1):55-72. doi: 10.1615/critreveukaryotgeneexpr.v13.i1.50.
Oxalate is a major component of the most common form of kidney stones--calcium oxalate stones. High concentrations of oxalate promote stone formation in two ways: (1) by providing urinary conditions favorable to the formation of calcium oxalate crystals, and (2) by inducing renal injury that generates cellular debris and promotes crystal nucleation and attachment. Oxalate toxicity is mediated in part by activation of lipid signaling pathways that produce arachidonic acid, lysophospholipids, and ceramide. These lipids disrupt mitochondrial function by increasing reactive oxygen species (ROS), decreasing mitochondrial membrane potential, and increasing mitochondrial permeability. The net response is cytochrome C release, activation of caspases, and apoptosis or necrosis. Not all cells succumb to oxalate toxicity, however, in those cells that don't, ROS and lipid-signaling molecules induce changes in gene expression that allow them to survive and adapt to the toxic insult. The increased expression of immediate early genes (IEGs), osteopontin, extracellular matrix (ECM) proteins, crystallization inhibitors, and chemokines orchestrates a group of cellular responses--including cell proliferation, secretion of kidney stone inhibitory proteins, recruitment of immune cells, and tissue remodeling--that limit accumulation of cell debris or increase the production of inhibitors of calcium oxalate crystallization, thereby limiting stone formation.
草酸盐是最常见的肾结石类型——草酸钙结石的主要成分。高浓度草酸盐通过两种方式促进结石形成：（1）通过提供有利于草酸钙晶体形成的尿液条件，以及（2）通过诱导肾损伤，产生细胞碎片并促进晶体成核和附着。草酸盐毒性部分由激活产生花生四烯酸、溶血磷脂和神经酰胺的脂质信号通路介导。这些脂质通过增加活性氧（ROS）、降低线粒体膜电位和增加线粒体通透性来破坏线粒体功能。最终反应是细胞色素C释放、半胱天冬酶激活以及细胞凋亡或坏死。然而，并非所有细胞都会死于草酸盐毒性，在那些未受影响的细胞中，ROS和脂质信号分子会诱导基因表达变化，使它们能够存活并适应毒性损伤。立即早期基因（IEGs）、骨桥蛋白、细胞外基质（ECM）蛋白、结晶抑制剂和趋化因子的表达增加，协调了一组细胞反应——包括细胞增殖、肾结石抑制蛋白的分泌、免疫细胞的募集和组织重塑——这些反应限制了细胞碎片的积累或增加了草酸钙结晶抑制剂的产生，从而限制了结石形成。
