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Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys

Departments of ¹Human Nutritional Sciences and ²Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba

Submitted 17 August 2005 ; accepted in final form 12 October 2005

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 B₂ (TXB₂, stable metabolite of TXA₂), prostaglandin E₂ (PGE₂), and 6-keto-prostaglandin F₁ (6-keto-PGF₁, stable metabolite of PGI₂)] 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·min^–1·mg protein^–1 (P < 0.001)] and COX-2 [0.64 ± 0.10 vs. 2.32 ± 0.22 ng prostanoids·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 2–10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB₂ > 6-keto-PGF₁ > PGE₂, as determined by higher renal prostanoid levels and COX activity ratios of TXB₂/6-keto-PGF₁, TXB₂/PGE₂, and 6-keto-PGF₁/PGE₂. 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.

thromboxane; prostaglandin

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				D. Sankaran, N. Bankovic-Calic, M. R. Ogborn, G. Crow, and H. M. Aukema Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease Am J Physiol Renal Physiol, September 1, 2007; 293(3): F821 - F830. [Abstract] [Full Text] [PDF]