Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper oil.
BACKGROUND
Calcineurin-inhibitor nephrotoxicity plays a role in the pathogenesis of chronic allograft nephropathy by causing renal ischemia mediated by vasoconstrictive metabolites of the prostanoid pathway. The purpose of our study was to evaluate whether altering the prostanoid profile using juniper oil (JO) would afford renoprotection in rats treated with tacrolimus.


METHODS
Diets supplemented with biologic oils (no supplementation, JO, fish oil [FO], safflower oil [SO], and arachidonic acid [AA]) were fed to five groups of rats for 5 weeks; during the last 2 weeks, tacrolimus was administered to all groups except for a control group of animals. At week 5, urinary prostaglandin (PG)F(2-alpha) and inulin clearances were measured. The rat kidneys were harvested to determine the renal cell membrane composition for arachidonic, eicosatrienoic, and eicosapentaenoic acids.


RESULTS
Both JO and FO completely reversed the decrease in inulin clearance seen with tacrolimus, the greatest effect being with JO (inulin clearance 15.1+/-3 vs. 6.0+/-1.1 ml/min in the nonsupplemented group; P<0.001); urinary PGF(2-alpha) excretion was also highest in the JO group (328+/-23 pg/mL, P<0.001 vs. the nonsupplemented group). Fatty acid membrane analysis showed greatest incorporation of eicosapentaenoic and eicosatrienoic acids in the JO- (5.7+/-0.6% and 3.1+/-0.4%, respectively) and FO- (8.1+/-0.7% and 2.8+/-0.6%, respectively) treated animals.


CONCLUSIONS
JO supplementation in tacrolimus-treated rats was associated with incorporation of vasodilatory prostanoids in the renal-cell membrane and elevated urinary PGF(2-alpha) excretion, and the precipitous fall in inulin clearance induced by tacrolimus was completely prevented. Whether this benefit will translate into a reduction in chronic allograft nephropathy remains to be determined. However, our preliminary data point towards the need for human trials.
Butani
Lavjay
L
Section of Pediatric Nephrology, University of California, Davis Medical Center, Sacramento, CA 95817, USA. lavjay.butani@ucdmc.ucdavis.edu.
Afshinnik
Arash
A
Johnson
Jeremy
J
Javaheri
Daniel
D
Peck
Schonze
S
German
J Bruce
JB
Perez
Richard V
RV
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001835:Body Weight; D002462:Cell Membrane / Q000737:chemistry; D015237:Dinoprost / Q000652:urine; D004347:Drug Interactions; D005227:Fatty Acids / Q000032:analysis; D005395:Fish Oils / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007444:Inulin / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D010938:Plant Oils / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012450:Safflower Oil / Q000494:pharmacology; D016559:Tacrolimus / Q000633:toxicity*
D005227:Fatty Acids; D005395:Fish Oils; D007166:Immunosuppressive Agents; D010938:Plant Oils; D016718:Arachidonic Acid; D012450:Safflower Oil; D007444:Inulin; D015237:Dinoprost; C115013:juniper berry oil; D016559:Tacrolimus