Mechanisms mediating oxalate-induced alterations in renal cell functions.
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.
Jonassen
Julie A
JA
Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Julie.Jonassen@umassmed.edu
Cao
Lu-Cheng
LC
Honeyman
Thomas
T
Scheid
Cheryl R
CR
D000222:Adaptation, Physiological; D000818:Animals; D002129:Calcium Oxalate / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007669:Kidney Calculi / Q000139:chemically induced* / Q000378:metabolism; D050356:Lipid Metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D053495:Osteopontin; D010070:Oxalates / Q000378:metabolism* / Q000633:toxicity; D017382:Reactive Oxygen Species; D012795:Sialoglycoproteins / Q000032:analysis
D010070:Oxalates; D017382:Reactive Oxygen Species; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; D002129:Calcium Oxalate