Scheid C, Honeyman T, Kohjimoto Y, Cao L C, Jonassen J
Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Mol Urol. 2000 Winter;4(4):371-82.
Many studies on the etiology of stone disease have focused on the properties of urine that affect crystal nucleation and growth. More recent studies have focused on the properties of the renal epithelium and the role of injury in crystal retention. The latter studies have shown that oxalate exposure per se can damage renal epithelial cells and enhance crystal binding. This overview summarizes findings of specific biochemical and genetic alterations observed in renal epithelial cells after exposure to oxalate. In LLC-PK1 and MDCK cells, oxalate exposure produces marked effects on membranes, causing a redistribution of phosphatidylserine and activation of two lipid signaling cascades, one involving phospholipase A(2) (PLA(2)) and one involving ceramide. Longer exposure to oxalate leads to membrane damage and cell death. Adaptive responses are also observed, including proliferation (for replacement of damaged cells) and induction of various genes (for cellular replacement and repair). Many or all of these responses are blocked by antioxidants, and many can be mimicked by PLA(2) agonists/products. This finding suggests links between oxalate-induced increases in oxidant stress, lipid signaling pathways, and subsequent molecular responses that may eventuate in renal cell damage or death. Whether such changes play a role in stone disease in vivo, and whether strategies to inhibit these changes would be beneficial therapeutically, is unknown.
许多关于结石病病因的研究都集中在影响晶体成核和生长的尿液特性上。最近的研究则聚焦于肾上皮细胞的特性以及损伤在晶体滞留中的作用。后一类研究表明，草酸盐本身的暴露会损害肾上皮细胞并增强晶体结合。本综述总结了暴露于草酸盐后在肾上皮细胞中观察到的特定生化和基因改变的研究结果。在LLC-PK1和MDCK细胞中，草酸盐暴露对细胞膜产生显著影响，导致磷脂酰丝氨酸重新分布并激活两个脂质信号级联反应，一个涉及磷脂酶A2（PLA2），另一个涉及神经酰胺。长时间暴露于草酸盐会导致细胞膜损伤和细胞死亡。还观察到适应性反应，包括增殖（用于替换受损细胞）和诱导各种基因（用于细胞替换和修复）。许多或所有这些反应都被抗氧化剂阻断，并且许多反应可以被PLA2激动剂/产物模拟。这一发现表明草酸盐诱导的氧化应激增加、脂质信号通路以及随后可能导致肾细胞损伤或死亡的分子反应之间存在联系。这些变化在体内结石病中是否起作用，以及抑制这些变化的策略在治疗上是否有益，目前尚不清楚。
