Background: Prostaglandins such as prostaglandin E(2) (PGE(2)) and prostaglandin I(2) (PGI(2)) counteract the angiotensin II (Ang II)-induced vasoconstriction in the glomerular microcirculation. We have shown that Ang II promotes mesangial cell hypertrophy via reactive oxygen species (ROS), which originate from nicotinamide adenine dinucleotide phosphate and its reduced form (NADH/NADPH) oxidase. It has been reported that conditions associated with activation of the renin-angiotensin system result in increased glomerular cyclooxygenase-2 (COX-2) expression and activity.
Methods: We designed studies to determine (1) whether Ang II induces COX-2 in the glomerulus in vivo in the glomerulus as well as in vitro in mesangial cells, (2) whether ROS originated from Ang II are involved, and (3) whether COX-2-derived prostaglandins modulate the growth promoting effects of Ang II in mesangial cells. Rats were infused with Ang II (0.7 mg/kg/day) for 5 days and glomerular COX-2 expression and activity assessed in isolated glomeruli.
Results: Ang II increased glomerular PGE(2) production (100%) accompanied by a concomitant increase in glomerular COX-2 expression at the mRNA (1.7-fold) and protein level (sixfold). In mesangial cells, Ang II significantly increased mesangial cell PGE(2) (200%) and PGI(2) (100%) production as well as COX-2 mRNA that was prevented by the angiotensin type 1 (AT1) receptor blocker irbesartan and the COX-2 inhibitor NS-398. The NADPH oxidase inhibitor diphenyleneiodonium (DPI), the ROS scavenger tiron as well as catalase, inhibited Ang II-induced PGE(2) production suggesting that Ang II-induced ROS mediate COX-2 up-regulation. Strikingly, COX-2 inhibition as well as blockade of the type 1 PGE(2) receptor (EP1) prevented Ang II-induced mesangial cell hypertrophy suggesting that COX-2-derived prostaglandins, and specifically PGE(2), importantly contribute to the growth promoting effects of Ang II.
Conclusion: These studies suggest that blockade of specific PGE(2) receptors may be a novel strategy to modulate the pathologic effects of COX-2-derived prostaglandins without simultaneously affecting protective vasodilatory mechanisms.