Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys.
Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley-cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B(2) (TXB(2), stable metabolite of TXA(2)), prostaglandin E(2) (PGE(2)), and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), stable metabolite of PGI(2))] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 +/- 0.02 vs. 0.45 +/- 0.11 ng prostanoids x min(-1) x mg protein(-1) (P < 0.001)] and COX-2 [0.64 +/- 0.10 vs. 2.32 +/- 0.22 ng prostanoids x min(-1).mg protein(-1) (P < 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were approximately 2-10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB(2) > 6-keto-PGF(1alpha) > PGE(2), as determined by higher renal prostanoid levels and COX activity ratios of TXB(2)/6-keto-PGF(1alpha), TXB(2)/PGE(2), and 6-keto-PGF(1alpha)/PGE(2). This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms.
Warford-Woolgar
Lori
L
Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada.
Peng
Claudia Yu-Chen
CY
Shuhyta
Jamie
J
Wakefield
Andrew
A
Sankaran
Deepa
D
Ogborn
Malcolm
M
Aukema
Harold M
HM
D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D020869:Gene Expression Profiling; D007527:Isoenzymes; D007674:Kidney Diseases / Q000503:physiopathology*; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D011453:Prostaglandins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2