Tubuloglomerular feedback is decreased in COX-1 knockout mice after chronic angiotensin II infusion.
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.
Araujo
Magali
M
Division of Nephrology and Hypertension, Department of Medicine, Georgetown University, 4000 Reservoir Road, Washington, DC 20057, USA.
Welch
William J
WJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension; D007678:Kidney Glomerulus / Q000502:physiology*; D007684:Kidney Tubules / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011453:Prostaglandins / Q000378:metabolism
D008565:Membrane Proteins; D011453:Prostaglandins; D000804:Angiotensin II; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse