Introduction
The activity of cyclooxygenase 2 (COX-2) is required for normal postnatal kidney development in the rat. Pharmacological inhibition of the renin-angiotensin system leads to similar morphological alterations in developing rat kidneys as COX-2 inhibition or COX-2 gene deletion. This suggests a serial coupling between the renin-angiotensin system and the prostaglandin cascade in postnatal development of the rat kidney. We tested the hypothesis that the renin-angiotensin system regulates the activitity of COX-2 in the rat kidney in the postnatal period.
Methods
Plasma renin concentration and kidney tissue renin concentration was measured by radioimmunoassay in a series of embryonal (day e17 and e19) and postnatal (p0, p1, p3, p7, p14, p21, p28, p56) rats. COX-2 and renin mRNA expression was assessed by semiquantitative ribonuclease protection assay. COX-2 protein was determined by western blotting analysis. To inihibit the renin angiotensin system rats were given the angiotensin II (ANG II) receptor antagonist candesartan (1 mg/kg*day) or the aldosterone antagonist canrenon (20 mg/kg*day) from p1 to p5. Controls were injected with vehicle.
Results
Plasma renin concentration and renin mRNA expression peaked at day p0-p1 and declined to reach adult levels at p14. In contrast, COX-2 mRNA was hardly detectable until p7, where there was a ca. hundred-fold increase in mRNA level compared to embryonal and early postnatal levels. The elevated COX-2 levels were maintained through the period p7 to p28. At p56 renal COX-2 mRNA had reached low levels as in mature control rats. Treating rats with candesartan from p1 to p5 resulted in a marked elevation of plasma renin concentration (up to 70-fold) and a 10-fold elevation of renin mRNA expression. COX-2 mRNA abundance was increased 3-fold in response to candesartan. In contrast the aldosterone antagonist canrenone did not change plasma renin concentration, renin mRNA or COX-2 mRNA expression
Conclusions
We conclude that COX-2 and renin are developmentally regulated gene products and that the activity of the renin angiotensin system and of COX-2 are inversely correlated in the early postnatal period. As observed in adult animals, ANG II exerts a negative feed back on the expression of COX-2 in the perinatal period. Thus, it is conceivable that the decrease in activity of the renin-angiotensin system from p0 to p7 is involved in the induction of COX-2 at p7.
References