title: Distinct roles for basal and induced COX-2 in podocyte injury.
abstract: Transgenic mice that overexpress cyclooxygenase-2 (COX-2) selectively in podocytes are more susceptible to glomerular injury by adriamycin and puromycin (PAN). To investigate the potential roles of COX-2 metabolites, we studied mice with selective deletion of prostanoid receptors and generated conditionally immortalized podocyte lines from mice with either COX-2 deletion or overexpression. Podocytes that overexpressed COX-2 were virtually indistinguishable from wild-type podocytes but were significantly more sensitive to PAN-induced injury, produced more prostaglandin E(2) and thromboxane B(2), and had greater expression of prostaglandin E(2) receptor subtype 4 (EP(4)) and thromboxane receptor (TP). Treatment of COX-2-overexpressing podocytes with a TP antagonist reduced apoptosis, but treatment with an EP(4) antagonist did not. In contrast, podocytes from COX-2-knockout mice exhibited increased apoptosis, markedly decreased cell adhesion, and prominent stress fibers. In vivo, selective deletion of podocyte EP(4) did not alter the increased sensitivity to adriamycin-induced injury observed in mice overexpressing podocyte COX-2. In contrast, genetic deletion of TP in these mice prevented adriamycin-induced injury, with attenuated albuminuria and foot process effacement. These results suggest that basal COX-2 may be important for podocyte survival, but overexpression of podocyte COX-2 increases susceptibility to podocyte injury, which is mediated, in part, by activation of the thromboxane receptor.
authors: Division of Nephrology, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, TN 37232, USA.
authors: Huifang
authors: H
authors: Cheng
authors: Xiaofeng
authors: X
authors: Fan
authors: Youfei
authors: Y
authors: Guan
authors: Gilbert W
authors: GW
authors: Moeckel
authors: Roy
authors: R
authors: Zent
authors: Raymond C
authors: RC
authors: Harris
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity; D005921:Glomerulonephritis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D011691:Puromycin / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000235:genetics / Q000378:metabolism; D013931:Thromboxanes / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D011691:Puromycin; D004317:Doxorubicin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone