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-PGF1alpha 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 microEq/min) and nonclipped kidneys (from 5.4 +/- 0.5 to 2.9 +/- 0.3 microEq/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.