Activation of the RAAS is a fundamental mechanism to counteract a decrease of extracellular volume due to diminished NaCl intake or a loss of blood. In this context, a chronic challenge leads to a marked increase of circulating renin, what reflects an increase of renin-expressing cells within the kidney. The recruitment of renin cells comprises two distinct components, namely a transformation of vascular smooth muscle cells in the afferent arteriole into renin producers and an induction of renin expression in perivascular cells of the juxtaglomerular apparatus (JGA). The latter is commonly referred to as juxtaglomerular hypertrophy. We recently reported that the recruitment of VSMCs in the afferent arterioles is likely dependent to a NO-GC related signaling pathway, which however, does not affect renin expression in the perivascular juxtaglomerular area. Therefore the mechanisms leading to JGA hypertrophy remain obscure. Upregulated renin expression depends on elevated levels of intracellular cyclic AMP, which can be achieved by prostanoid signaling via PGE2-EP4 receptors, at least during salt depletion. Since the macula densa expresses cyclooxygnease- 2 (COX-2) paracrine signaling from MD to the juxtaglomerular perivascular area would be conceivable to induce JGA hypertrophy.

To test this hypothesis we treated C57Bl6 wildtype mice to low salt diet in combination with ACE-inhibition to induce JGA-hypertrophy and administered the selective COX-2 inhibitor SC236 for 3 weeks. Treatment of C57Bl6 wildtype mice with low salt diet and ACE-inhibition increased renin mRNA abundance and number of renin expressing cells up to fivefold. These increases were moderately attenuated by COX-2 inhibition (about 20%). Similarly, the plasma renin concentration, which was 10-fold increased by treatment with the ACE-inhibitor in combination with low salt diet, was reduced by about 20% by COX-2 inhibition, suggesting that the effect of COX-2 inhibition on renin secretion is indirectly mediated by the effect on the number of renin-expressing cells.

We conclude that paracrine signaling by COX-2 derived prostanoids contributes to but does not essentially mediate JGA-hypertrophy in states of salt depletion induced by RAAS-inhibition.