Tubuloglomerular feedback (TGF) is decreased in COX‐1 knockout mice after chronic angiotensin II (Ang II) infusion

Abstract

Prostaglandins (PGs) are important modulators of renal hemodynamics. PGE2 and PGI2 are the major PGs in the renal cortex of mice and acute infusion of Ang II induces a COX‐2 dependent increase of these PGs. Prostaglandin E synthase (PGES) is coexpressed with COX‐2 in the macula densa (MD). We previously showed that MD COX‐2 modulates TGF responses in the rat. Genetic deletion of COX‐1 is associated with renal vasoconstriction, decreased renal and urinary PGs and attenuated ang II‐induced hypertension. However, the effects of lower levels of Ang II in the absence of COX‐1 are not known. The present study was designed to evaluate the effects of slow pressure doses of Ang II (400 ng/kg/min) on TGF in COX‐1 knockout mice. Four groups of mice were studied: 1) COX‐1 wild type (WT) ; 2) COX‐1 knockout (KO); 3) WT infused with Ang II for 14 days; 4) COX‐1 KO infused with Ang II for 14 days. Chronic Ang II infusion increased significantly TGF in WT mice (WT: 9.3±0.7 vs WT+AngII: 12.2±1.7 mmHg, p<0.001). However, chronic ang II decreased TGF in COX‐1 KO mice (KO: 11.0±1.2 vs KO+AngII: 8.3±0.6 mmHg, p<0.01). Ang II infusion increased MAP similarly in both groups (WT: 93±2 vs KO: 91±3 mmHg, NS, n=6 mice). These data demonstrate the effects of MD COX‐2 production of PGs in the absence of COX‐1 and their influence in TGF. During chronic Ang II infusion, TGF is increased in WT mice, but reduced in COX‐1 KO mice. This suggests that COX‐1 is stimulated by Ang II and produces vasoconstricting PGs. In the absence of COX‐1, COX‐2 produces primarily vasodilating PGs in response to Ang II, resulting in a lower TGF. These data further demonstrate that PGs generated by both COX isoforms regulate TGF.