Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice.
Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A(2)) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH(2), and 8-iso-PGF(2alpha), but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF(2alpha) were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.
Michel
Frédéric
F
Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
Simonet
Serge
S
Vayssettes-Courchay
Christine
C
Bertin
Florence
F
Sansilvestri-Morel
Patricia
P
Bernhardt
Fabienne
F
Paysant
Jérôme
J
Silvestre
Jean-Sébastien
JS
Levy
Bernard I
BI
Félétou
Michel
M
Verbeuren
Tony J
TJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D013311:Streptozocin; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D001057:Apolipoproteins E; D009281:Naphthalenes; D011422:Propionates; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C075750:8-epi-prostaglandin F2alpha; D013311:Streptozocin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C501362:terutroban; D015237:Dinoprost; D011464:Epoprostenol; D008729:Methoxamine; D000109:Acetylcholine