Renal cyclooxygenase-2 in obese Zucker (fatty) rats.
BACKGROUND
Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A(2) (TxA(2)) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes.


METHODS
Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E(2) (PGE(2)) and TxA(2), in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12).


RESULTS
Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 +/- 130%) (P < 0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 +/- 120%) (P < 0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30% lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 mug/kg), used as inhibitor of insulin signaling.


CONCLUSIONS
Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.
Komers
Radko
R
Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. radko.komers@medicon.cz
Zdychová
Jana
J
Cahová
Monika
M
Kazdová
Ludmila
L
Lindsley
Jessie N
JN
Anderson
Sharon
S
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007668:Kidney / Q000201:enzymology*; D008565:Membrane Proteins; D009765:Obesity / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis* / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D013929:Thromboxane B2 / Q000096:biosynthesis; D000077191:Wortmannin
D000730:Androstadienes; D005230:Fatty Acids, Nonesterified; D008565:Membrane Proteins; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone; D000077191:Wortmannin