Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids.

Area of Science:

• Cardiovascular Research
• Renal Physiology
• Endothelial Biology

Background:

• Endothelium-derived hyperpolarizing factors, including epoxyeicosatrienoic acids (EETs), are crucial for vascular function.
• Endothelial dysfunction underlies hypertension and associated renal dysfunction.
• Midkine (MK) has been implicated in enhancing hypertension in chronic kidney disease (CKD).

Purpose of the Study:

• To investigate the role of midkine (MK) in regulating epoxyeicosatrienoic acid (EET) activity.
• To determine the impact of the MK/EET pathway on blood pressure (BP) and renal function.
• To explore the potential of the MK/EET pathway as a therapeutic target for hypertension.

Main Methods:

• Utilized MK gene-deleted mice and wild-type mice in a uninephrectomy model.
• Administered nitric oxide synthase (NOS) inhibitor to induce hypertension.
• Employed anti-MK antibody to assess the effect of MK inhibition.
• Measured EET levels, BP, glomerulosclerosis, proteinuria, and renal blood flow.

Main Results:

• MK gene deletion conferred resistance to hypertension and reduced renal damage after NOS inhibition.
• Anti-MK antibody ameliorated hypertension in uninephrectomized wild-type mice.
• MK-deficient mice exhibited higher EET production and EETs dominantly regulated their BP and renal blood flow.
• MK administration to deficient mice restored wild-type BP control.

Conclusions:

• The midkine (MK)/epoxyeicosatrienoic acid (EET) pathway is integral to physiological blood pressure (BP) regulation.
• MK negatively regulates EET production and activity, influencing BP and renal hemodynamics.
• This pathway represents a potential therapeutic target for hypertension in the context of endothelial dysfunction.