Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria.
OBJECTIVE
To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes.


METHODS
Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured.


RESULTS
Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age.


CONCLUSIONS
These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.
Dey
Aparajita
A
Vascular Biology Center, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA 30912, USA.
Williams
Roger S
RS
Pollock
David M
DM
Stepp
David W
DW
Newman
John W
JW
Hammock
Bruce D
BD
Imig
John D
JD
D000419:Albuminuria / Q000201:enzymology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D051546:Cyclooxygenase 2; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D000072467:Cytochrome P450 Family 2; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000209:etiology; D006973:Hypertension / Q000201:enzymology / Q000209:etiology; D007527:Isoenzymes / Q000032:analysis*; D007668:Kidney / Q000098:blood supply; D007672:Kidney Cortex / Q000201:enzymology; D007678:Kidney Glomerulus / Q000201:enzymology; D008297:Male; D008833:Microcirculation / Q000201:enzymology; D009765:Obesity / Q000150:complications / Q000201:enzymology* / Q000652:urine*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D051381:Rats; D011924:Rats, Zucker; D039181:Steroid 16-alpha-Hydroxylase / Q000032:analysis; D013929:Thromboxane B2 / Q000652:urine
D001786:Blood Glucose; C000717351:Cyp2c23 protein, rat; D007527:Isoenzymes; C400322:cytochrome P-450 CYP2C subfamily; D013929:Thromboxane B2; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases