Everolimus treatment downregulates renocortical cyclooxygenase-2 expression in the rat kidney.
Based on recent evidence that renal cyclooxygenase-2 (COX-2) gene expression is suppressed by immunosuppressive agents such as cyclosporin A (CsA), tacrolimus and dexamethasone, this study aimed to characterize the effect of the new immunosuppressant everolimus on COX-2 expression in the rat kidney. Oral application of everolimus (3 mg kg(-1) day(-1)) to male Sprague-Dawley rats (175-200 g; n=8) for 7 days lowered COX-2 expression in the rat renal cortex and outer medulla, while COX-2 expression in the inner medulla as well as COX-1 expression remained unaltered. Furthermore, everolimus decreased renocortical prostaglandin (PG) E(2) concentration. Everolimus also attenuated the stimulation of renocortical COX-2 expression by furosemide (12 mg day(-1) for 7 days; s.c. via osmotic minipumps), by low salt intake (0.02% NaCl, wt wt(-1)) or by a combination of low salt intake with the AT(1)-receptor antagonist valsartan (30 mg kg(-1) day(-1); oral). In line with these findings, everolimus decreased renocortical PGE(2) concentration during these treatment maneuvers. Everolimus moderately increased natriuresis and diuresis, while the urinary excretion of PGE(2), 6-keto PGF(1alpha) and thromboxane B(2) was decreased. These findings suggest that everolimus inhibits basal and also stimulated expression of renocortical COX-2 and of tissue prostanoid formation. Since inhibition of renal prostanoid formation by everolimus was associated by an increased rather than decreased natriuresis and diuresis, it appears as if everolimus also inhibits tubular salt and water resorption.
Höcherl
Klaus
K
Institut für Pharmazie, Lehrstuhl für Pharmakologie und Toxikologie, Universität Regensburg, Universitätsstrasse 31, D-93040 Regensburg, Germany. klaus.hoecherl@chemie.uni-regensburg.de
Hensel
Corina
C
Ulbricht
Bettina
B
Krämer
Bernhard K
BK
D000818:Animals; D003404:Creatinine / Q000097:blood / Q000652:urine; D015536:Down-Regulation; D000068338:Everolimus; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D011188:Potassium / Q000652:urine; D011453:Prostaglandins / Q000652:urine; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
D007166:Immunosuppressive Agents; D011453:Prostaglandins; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D000068338:Everolimus; D012964:Sodium; D003404:Creatinine; D011188:Potassium; D020123:Sirolimus