Tubuloglomerular feedback is decreased in COX-1 knockout mice after chronic angiotensin II infusion

Abstract

Prostaglandins (PGs), produced by two isoforms of cyclooxygenase (COX), COX-1 and COX-2, are important modulators of renal hemodynamics. COX-1 and COX-2 are expressed in the kidney often at distinct sites. Thromboxane (TxA(2)), PGE(2), and prostacyclin (PGI(2)) are the major PGs in the renal cortex of mice. Acute infusion of the vasoconstrictor ANG II increases COX-2-dependent PGE(2) and PGI(2). COX-2 is primarily expressed in the macula densa (MD), where several PG synthases are also expressed. We previously showed that MD COX-2 products modulate tubuloglomerular feedback (TGF) in the rat. Genetic deletion of COX-1 enhances COX-2 production of PGs, decreases renal and urinary PGs, and attenuates ANG II-induced hypertension. The present study tested the effects of chronic ANG II infusion on TGF in COX-1 knockout (KO) mice. Basal TGF was similar in COX-1 KO and wild-type (WT) mice. Chronic ANG II infusion increased TGF in WT mice (WT: 9.3 +/- 0.7 vs. WT + ANG II: 12.2 +/- 1.6 mmHg, P < 0.02). However, chronic ANG II decreased TGF in COX-1 KO mice (KO: 11.4 +/- 1.1 vs. KO + ANG II: 8.3 +/- 0.6 mmHg, P < 0.01). Pretreatment with the COX-2 inhibitor SC-58,236 in COX-1 KO mice prevented the ANG II-associated reduction in TGF (11.4 +/- 1.0 vs. 11.5 +/- 0.28 mmHg, not significant). Excretion of 6-keto-PGF(2alpha), the metabolite of PGI(2), was increased by ANG II infusion, whereas excretion of TxB(2), the stable metabolite of TxA(2), was not changed. ANG II infusion increased mean arterial pressure similarly in both WT and KO mice (WT: 93 +/- 2 vs. KO: 92 +/- 3 mmHg), but not in KO mice pretreated with SC-58,236 (85 +/- 2 mmHg). This study shows that COX-1-generated PGs partially mediate ANG II increases in TGF and that COX-2 PGs offset that effect.

Fig. 1.

Excretion of thromboxane B₂ (TxB₂), the metabolite of thromboxane A₂, PGE₂ and 6-keto-PGF_2α, the stable metabolite of prostacyclin in cyclooxygenase (COX)-1 −/− (black) and COX-1 −/− mice treated with angiotensin II for 2 wk (open). **P < 0.01 compared with COX-1 −/−. ***P < 0.001 compared with COX-1 −/−.

Fig. 2.

Changes in stop-flow pressure (P_SF) in response to increased perfusion of loop of Henle (LH) from 0 to 30 nl/min. Thin lines represent individual nephrons and solid circles connected with bold line represent means ± SE. COX-1 +/+ mice (A, n = 6 mice/18 tubules) and COX-1 −/− mice (B, n = 6 mice/17 tubules).

Fig. 3.

Maximal tubuloglomerular feedback (TGF) responses (change in P_SF in LH perfusion of 0 and 30 nl/min) in COX-1 wild-type (WT; n = 6 mice/18 tubules), COX WT treated with ANG II (n = 6/23), COX knockout (KO; n = 6/17), and COX KO treated with ANG II (n = 7/23).

Fig. 4.

Maximal TGF responses in COX KO treated with ANG II (n = 7/23) and COX KO treated with ANG II and SC-58, 236 (SC; n = 6/17).