The effect of cyclosporine on agonist-stimulated glomerular and mesangial cell vasodilatory prostaglandin production.
Cyclosporine A administration produces an increase in renal vascular resistance and a decrease in glomerular filtration rate in both human and animal models. CsA usage in humans has also been shown to alter the ability of the kidney to adapt to alterations in renal hemodynamics. CsA alters the production of prostaglandins by isolated rat glomeruli. Normally, vasoconstrictive agents stimulate the production of vasodilatory glomerular and mesangial cell PG. To determine if CsA alters glomerular and mesangial cell (MC) vasodilatory PG production in response to vasoconstrictive agents, we administered CsA, 20 mg/kg, or vehicle to rats for 7 days, or incubated mesangial cells with CsA 1 mcg/ml for 24 hr. Ex vivo glomerular PGE2 and 6-keto-PGF1a production was determined in the presence or absence of angiotensin II 10(-6) M and norepinephrine 10(-5)M. CsA administration decreased glomerular production of both eicosanoids in the basal and stimulated state. Incubation of MC with CsA markedly suppressed PGE2 and 6-keto-PGF1a production in response to stimulation with 200 nM angiotensin II. To determine if CsA inhibits angiotensin II-stimulated PG production prior to protein kinase C, we incubated glomeruli and MC with the diacylglycerol mimetic OAG. CsA depressed OAG-stimulated glomerular and MC PGE2 and 6-keto-PGF1a production. Conversely, CsA stimulated the production of PGE2 by renal medullary slices. We conclude that CsA blunts the vasoconstrictor-induced increase in glomerular and mesangial cell vasodilatory PG production, thereby removing a compensatory mechanism that maintains GFR in states of vasoconstrictor excess.
Department of Medicine, University of Louisville, Kentucky.
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Bunke
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Wilder
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Martin
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D003401:Creatine / Q000652:urine; D016572:Cyclosporine / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007679:Kidney Medulla / Q000033:anatomy & histology / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D011453:Prostaglandins; D014665:Vasodilator Agents; D000804:Angiotensin II; D015121:6-Ketoprostaglandin F1 alpha; D016572:Cyclosporine; D011493:Protein Kinase C; D015232:Dinoprostone; D003401:Creatine; D009638:Norepinephrine