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Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper oil
Lavjay Butani1, Arash Afshinnik, Jeremy Johnson
1Section of Pediatric Nephrology, University of California, Davis Medical Center, Sacramento, CA 95817, USA. lavjay.butani@ucdmc.ucdavis.edu.
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.
Insights
Juniper oil (JO) supplementation prevented tacrolimus-induced kidney damage in rats by improving prostanoid profiles. This suggests JO may offer renoprotection against calcineurin-inhibitor nephrotoxicity.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Calcineurin inhibitors like tacrolimus can cause kidney damage (nephrotoxicity) contributing to chronic allograft nephropathy.
- This damage is linked to reduced blood flow (renal ischemia) caused by vasoconstrictive prostanoid metabolites.
- Altering the prostanoid profile may protect the kidneys.
Purpose of the Study:
- To investigate if juniper oil (JO) can protect rat kidneys from tacrolimus-induced damage.
- To evaluate the effect of JO on the prostanoid profile in rats treated with tacrolimus.
Main Methods:
- Rats were fed diets with different oils (no supplementation, JO, fish oil, safflower oil, arachidonic acid) for 5 weeks.
- Tacrolimus was administered during the last 2 weeks to all groups except a control.
- Kidney function (inulin clearance) and urinary prostaglandin F(2-alpha) were measured; kidney cell membranes were analyzed for fatty acids.
Main Results:
- Juniper oil (JO) and fish oil (FO) completely reversed tacrolimus-induced decreases in inulin clearance.
- JO showed the greatest renoprotective effect, significantly improving inulin clearance compared to the non-supplemented group.
- JO and FO diets led to increased incorporation of vasodilatory fatty acids (eicosapentaenoic and eicosatrienoic acids) in kidney cell membranes.
Conclusions:
- Juniper oil (JO) supplementation in rats treated with tacrolimus promoted vasodilatory prostanoids in kidney cell membranes.
- This resulted in elevated urinary prostaglandin F(2-alpha) and completely prevented the decline in kidney function caused by tacrolimus.
- Preliminary findings suggest JO may be beneficial and warrant human trials for chronic allograft nephropathy.