Selective enhancement of thromboxane in macrophages and kidneys in cyclosporine-induced nephrotoxicity. Dietary protection by fish oil.
Cyclosporine (CsA) associated renal dysfunction is related in part to renal vasoconstriction. To identify the role of cyclooxygenase metabolites in the induction of vasoconstriction, we analyzed the effect of CsA on the synthesis of thromboxane (TxA2) prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the kidney and peritoneal macrophages. Groups of rats were pair-fed diets enriched with 20% fish oil (FO) or corn oil (CO) for 4 weeks and then were injected with CsA 12.5 mg/kg/day i.p. for 2 weeks. CsA induced the synthesis of TxA2 and modestly reduced PGE2 and PGI2 in renal cortex and peritoneal macrophages. Feeding rats a diet enriched in FO containing omega-3 fatty acids as compared with CO without these fatty acids suppressed the increase in TxA2 and decreased the vasodilators PGE2 and PGI2 in the kidney and peritoneal macrophages, while modifying the decrease in the glomerular filtration rate and vacuolization in proximal convoluted tubules characteristic of rodent CsA-associated nephrotoxicity. Thus, CsA-initiated renal vasoconstriction is related to an increase in the vasoconstrictive Tx molecule and the reduction in vasodilator metabolites. Intrarenal macrophages represent a likely source of this Tx production. Feeding rats diets containing omega-3 fatty acids, known to be competitive inhibitors of cyclooxygenase metabolites, prevents CsA from selectively increasing TxA2 and preserves renal function.
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
T S
TS
Rogers
L
L
Elzinga
W M
WM
Bennett
V E
VE
Kelley
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D003524:Cyclosporins / Q000633:toxicity*; D004041:Dietary Fats / Q000627:therapeutic use*; D015232:Dinoprostone; D005395:Fish Oils / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000178:diet therapy / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011458:Prostaglandins E / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D013928:Thromboxane A2 / Q000096:biosynthesis*; D014661:Vasoconstriction
D003524:Cyclosporins; D004041:Dietary Fats; D005395:Fish Oils; D011458:Prostaglandins E; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone