Effect of hyperhomocysteinemia on plasma or tissue adenosine levels and renal function

Area of Science:

• Nephrology
• Cardiovascular Science
• Biochemistry

Background:

• Hyperhomocysteinemia (hHcys) is a known cardiovascular disease risk factor.
• Previous studies indicated hHcys causes glomerular dysfunction independently of hypertension.
• The precise mechanism behind hHcys's detrimental effects remained unclear.

Purpose of the Study:

• To investigate the hypothesis that hHcys causes pathogenic effects by reducing plasma or tissue adenosine (Ado) concentrations.
• To elucidate the mechanism linking hHcys to kidney dysfunction.

Main Methods:

• Acute hyperhomocysteinemia was induced in Sprague-Dawley rats via L-homocysteine infusion.
• Plasma and kidney dialysate adenosine levels were measured.
• Enzyme kinetics were analyzed to determine the effect on SAH hydrolase and 5'-nucleotidase.
• Renal function parameters (blood flow, GFR, excretion) were assessed and effects of an Ado receptor antagonist were evaluated.

Main Results:

• Intravenous L-homocysteine infusion significantly increased plasma homocysteine levels while decreasing plasma and renal adenosine levels.
• Chronic hHcys also resulted in significantly decreased plasma adenosine.
• Kinetic analysis indicated SAH hydrolase inhibition, not 5'-nucleotidase, was responsible for reduced renal adenosine.
• Homocysteine infusion impaired renal blood flow, GFR, and excretory function, effects reversed by an adenosine receptor antagonist.

Conclusions:

• Hyperhomocysteinemia leads to decreased plasma and tissue adenosine concentrations, primarily through SAH hydrolase inhibition.
• The reduction in adenosine is a key mechanism underlying the kidney dysfunction observed in hyperhomocysteinemia.
• Targeting adenosine pathways may offer a therapeutic strategy for managing hHcys-related cardiovascular complications.