Distinct role of intrarenal cyclooxygenase-1/2 in chronic unilateral renal ischemia

Aims: The role of cyclooxygenase (COX)-1/2-induced prostaglandins (PG) in unilateral chronic renal ischemia of anesthetized dogs was examined. Methods: Ischemic kidneys were established by reducing renal blood flow of left renal artery to 10% of baseline with an adjustable clip. After 4 weeks, changes in intrarenal contents of PGE2/PGI2 and angiotensin (Ang) II were evaluated with renal microdialysis and biopsy. Furthermore, the effect of a non-specific COX inhibitor (sulpyrine), a COX-2-specific inhibitor (NS398), and an Ang receptor antagonist (CS866) on renal function and renal PG contents were evaluated. Results: Unilateral renal artery clipping reduced renal plasma flow (RPF) in clipped (from 59 ± 2 to 17 ± 1 ml/min, n =18) and nonclipped kidneys (from 59 ± 2 to 44 ± 2 ml/min) and natriuresis. Intrarenal PGE2 increased only in clipped kidneys (from 114 ± 7 to 375 ± 25 pg/ml), whereas 6-keto-PGF1 α increased in both kidneys. Sulpyrine reduced intrarenal PG contents, and decreased RPF, GFR, and urinary sodium excretion (UNaV), whereas NS398 reduced UNaV in clipped (from 4.0 ± 0.9 to 1.7 ± 0.2 μEq/min) and nonclipped kidneys (from 5.4 ± 0.5 to 2.9 ± 0.3 μEq/min), without affecting renal hemodynamics. Intrarenal Ang II contents increased in clipped (from 0.70 ± 0.06 to 2.32 ± 0.33 pg/mg, n =18) and nonclipped kidneys (from 0.65 ± 0.06 to 2.45 ± 0.33 pg/mg, n =18), and CS866 improved renal hemodynamics and natriuresis. The elevated intrarenal Ang II content was suppressed by NS398 only in clipped kidneys. Conclusion: Unilateral renal ischemia elevates intrarenal PGE2 contents in clipped kidneys, which serves to countervail the aggravation of renal function. Furthermore, intrarenal COX isoforms may play differential roles, with COX-1 participating in modulation of renal hemodynamics, and COX-2 contributing to sodium excretion and Ang II formation.