Increased expression of renal cyclooxygenase-2 and neuronal nitric oxide synthase in hypertensive Cx40-deficient mice.
Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.
Krattinger
Nathalie
N
Department of Medicine, University Hospital, Lausanne, Switzerland.
Alonso
Florian
F
Capponi
Alessandro
A
Mazzolai
Lucia
L
Nicod
Pascal
P
Meda
Paolo
P
Haefliger
Jacques-Antoine
JA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017630:Connexins / Q000172:deficiency / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006973:Hypertension / Q000201:enzymology / Q000209:etiology*; D007668:Kidney / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012083:Renin / Q000097:blood; D000097003:Gap Junction alpha-5 Protein
D017630:Connexins; D051546:Cyclooxygenase 2; D052248:Nitric Oxide Synthase Type I; D011448:Prostaglandin Antagonists; D012333:RNA, Messenger; D012083:Renin; D000097003:Gap Junction alpha-5 Protein; C496321:Nos1 protein, mouse; C077623:Ptgs2 protein, mouse