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Renal function and vasomotor activity in mice lacking the Cyp4a14 gene
Paul Fidelis1, Leticia Wilson, Kayama Thomas
1Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
Experimental Biology and Medicine (Maywood, N.J.)
|October 15, 2010
Summary
Deletion of the Cyp4a14 gene in mice increases blood pressure and impairs kidney function. This study reveals that Cyp4a14 deficiency leads to elevated 20-hydroxyeicosatetraenoic acid (20-HETE) and nitric oxide (NO) imbalance, suggesting a prohypertensive state.
Area of Science:
- Nephrology
- Cardiovascular Physiology
- Molecular Endocrinology
Background:
- 20-hydroxyeicosatetraenoic acid (20-HETE) plays a role in regulating renal vascular tone and sodium reabsorption.
- Cytochrome P450 (Cyp) enzymes, specifically Cyp4a family members, are involved in 20-HETE synthesis in mice.
Purpose of the Study:
- To investigate the physiological consequences of Cyp4a14 gene deletion in mice.
- To evaluate the impact of Cyp4a14 deficiency on blood pressure, renal vascular responses, and tubular function.
Main Methods:
- Comparison of Cyp4a14 null (KO) mice with wild-type (WT) littermates.
- Assessment of systolic blood pressure, renal vascular reactivity to various agonists (angiotensin II, phenylephrine, KCl, guanosine 5'-O-(gamma-thio)triphosphate, NaF), and vasodilation (bradykinin, apocynin, sodium nitroprusside).
- Measurement of 20-HETE synthesis, nitric oxide (NO) production, lipid hydroperoxides, and vascular NADPH oxidase activity.
- Evaluation of renal excretory capacity following acute sodium load.
Main Results:
- Cyp4a14 KO mice exhibited elevated systolic blood pressure and enhanced vasoconstriction responses to GPCR agonists.
- KO kidneys showed blunted vasodilation to bradykinin and apocynin, alongside increased 20-HETE synthesis and reduced NO production.
- Evidence of endothelial nitric oxide synthase (eNOS) uncoupling, increased oxidative stress, and impaired sodium excretion capacity was observed in KO mice.
Conclusions:
- Deletion of the Cyp4a14 gene induces a prohypertensive state characterized by increased 20-HETE, eNOS uncoupling, oxidative stress, and impaired renal function.
- The Cyp4a14-deficient mouse serves as a valuable model for studying the complex interactions between NO and 20-HETE in regulating blood pressure and renal function.
