Peroxisome proliferator-activated receptor alpha and alpha/gamma agonists do not cause impairment in renal function in the rat.
OBJECTIVE
Patients treated with peroxisome proliferator-activated receptor analogs (PPAR) alpha or alpha/gamma may develop a transient and reversible increase in serum creatinine, the mechanism of which remains obscure. This study evaluates whether treatment with either PPAR-alpha or -alpha/gamma analogs, fenofibrate or tesaglitazar, may cause deterioration in renal hemodynamics or exert direct tubular or glomerular nephrotoxic effects in rats.


METHODS
Male Sprague-Dawley rats (300-320 g) were treated per os with fenofibrate (300 mg/kg/day), tesaglitazar (1.2 mg/kg/day) or vehicle, for 14 days. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by inulin clearance and ultrasonic flowmetry, and cumulative excretion of sodium and creatinine were assessed. Biomarkers of glomerular and tubular injury were measured, including urinary albumin excretion and renal mRNA levels of kidney injury molecule 1 (Kim-1), lipocalin 2 (Lcn2), and osteopontin (Spp1).


RESULTS
Fenofibrate and tesaglitazar improved the lipid profile, but caused no detectable decrease in GFR or RBF compared with vehicle-treated rats. Furthermore, the cumulative excretions of sodium and creatinine were not altered by the drugs. Finally, there was no significant difference between drug- and vehicle-treated groups in urinary albumin excretion or in the expression of renal injury biomarkers.


CONCLUSIONS
In the rat, no direct nephrotoxic effect or deterioration in renal hemodynamics and function were observed following treatment with fenofibrate or tesaglitazar.
Ovcharenko
Elena
E
Department of Physiology and Biophysics, Technion, Haifa, Israel.
Hansen
Michael K
MK
Goltsman
Ilia
I
Abu-Saleh
Niroz
N
Abassi
Zaid
Z
Walsh
Kathryn
K
Miele
Gino
G
Feuerstein
Giora Z
GZ
Winaver
Joseph
J
D000476:Alkanesulfonates / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics; D003404:Creatinine / Q000652:urine; D011345:Fenofibrate / Q000494:pharmacology* / Q000633:toxicity; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000633:toxicity; D007444:Inulin / Q000493:pharmacokinetics; D007684:Kidney Tubules / Q000187:drug effects* / Q000502:physiology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics; D008297:Male; D053495:Osteopontin / Q000235:genetics; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine
D000476:Alkanesulfonates; D015815:Cell Adhesion Molecules; D003404:Creatinine; D011345:Fenofibrate; D000960:Hypolipidemic Agents; D007444:Inulin; D000071068:Lipocalin-2; D054834:Lipocalins; D053495:Osteopontin; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D012333:RNA, Messenger; D012964:Sodium; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat; C506897:Spp1 protein, rat; C501413:tesaglitazar