Oxalate-induced changes in renal epithelial cell function: role in stone disease.
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.
Scheid
C
C
Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. cheyl.scheid@umassmed.edu
Honeyman
T
T
Kohjimoto
Y
Y
Cao
L C
LC
Jonassen
J
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D002455:Cell Division; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D051152:Clusterin; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism* / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007669:Kidney Calculi / Q000209:etiology* / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D053495:Osteopontin; D010070:Oxalates / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D000975:Antioxidants; D002518:Ceramides; D051152:Clusterin; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D018832:Molecular Chaperones; D010070:Oxalates; D010718:Phosphatidylserines; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D013109:Sphingomyelins; D014157:Transcription Factors; D053495:Osteopontin; D016718:Arachidonic Acid; D010741:Phospholipases A