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Updated: Jul 10, 2026
The Mouse Isolated Perfused Kidney Technique
Published on: November 17, 2016
Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice
Frédéric Michel1, Serge Simonet, Christine Vayssettes-Courchay
1Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
Abstract:
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.
Insights
Activation of thromboxane A(2) (TP) receptors contributes to kidney disease in atherosclerosis and diabetes. In diabetic mice, TP receptor-mediated vasoconstriction is increased, suggesting a role in early renal dysfunction.
Area of Science:
- Nephrology
- Cardiovascular Research
- Pharmacology
Background:
- Thromboxane A(2) (TP) receptor activation is implicated in atherosclerotic, diabetic, and renal diseases.
- Early kidney disease manifestations are linked to atherosclerosis.
Purpose of the Study:
- To investigate the role of TP receptors in renal vasoconstriction and vasodilation using isolated, perfused mouse kidneys.
- To analyze TP receptor function in wild-type, apolipoprotein E-deficient (ApoE-KO), and diabetic ApoE-KO mice.
Main Methods:
- Isolated, perfused mouse kidneys from C57BL6, ApoE-KO, and diabetic ApoE-KO mice were used.
- Changes in perfusion pressure were recorded in response to TP receptor ligands and other vasoactive agents.
- The selective TP receptor antagonist Triplion (S 18886) was employed to assess TP receptor involvement.
Main Results:
- TP receptor-mediated vasoconstrictions (to U 46619, arachidonic acid, PGH(2), 8-iso-PGF(2alpha)) were inhibited by Triplion, while responses to angiotensin II, endothelin, and norepinephrine were not.
- Acetylcholine and prostacyclin induced biphasic responses, with the constrictor component blocked by Triplion.
- Diabetic ApoE-KO mouse kidneys showed significantly augmented vasoconstrictions to U 46619 and 8-iso-PGF(2alpha) without changes in TP receptor expression or vasodilator activity.
Conclusions:
- TP receptors are functional in mouse kidneys and mediate vasoconstrictions to specific ligands, but not to angiotensin II, endothelin, or norepinephrine.
- TP receptor activation is involved in unusual vasoconstrictions induced by acetylcholine and prostacyclin.
- Increased TP receptor responsiveness in diabetic ApoE-KO kidneys suggests a role in the early development of kidney disease associated with diabetes and atherosclerosis.
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