Gene transfer approach in studying rat models of hypertension and diabetic organ damage

Tissue kallikrein is a serine proteinase that is known for its ability to process low molecular weight kininogen to release the vasoactive peptide hormone called kinin. Adrenomedullin (AM) is a 52-amino acid vasodilatory peptide. In order to examine the role of kallikrein/kinin and AM in volume-dependent hypertension, adenoviral vectors harboring either the kallikrein or AM gene were delivered to deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Kallikrein gene delivery delayed blood pressure increases for 3 weeks and achieved a maximum reduction of 50 mmHg. Kallikrein gene delivery also prevented renal damage as observed by a significant reduction in urinary protein levels and glomerular and tubular damage. AM gene delivery induced sustained blood pressure reduction, enhanced renal function and prevented renal damage. AM also protects against cardiac remodeling as evident by AM-mediated reduction in left ventricular weight, cardiomyocyte diameter and extracellular matrix formation. Significant increases in urinary and cardiac cAMP levels indicate activation of the target receptors. These findings show that kallikrein and AM protects against cardiovascular and renal damage in volume-overload hypertension, suggesting a possible therapeutic value in treatment of cardiovascular and renal diseases.; Diabetic cardiomyopathy ranges in severity from mild dysfunction to failure. AM gene transfer to STZ-diabetic rats showed significant improvements in cardiac function as observed by decreased left ventricle end diastolic pressure, increased cardiac output, cardiac index, heart rate and ±ΔP/Δt values. AM also reduced glycogen levels in both the heart and kidney, demonstrated by histological staining and chemical analysis. AM gene delivery resulted in reduction of renal tubular damage. Diabetic rats treated with AM also significantly gained body weight compared to STZ control rats. Increased cardiac cAMP levels along with increased cAMP and cGMP urinary levels occurred in rats receiving AM gene delivery. Western blot analysis revealed increased phosphorylated Akt in cardiac tissue and increased membrane-bound Glut4 levels in skeletal muscle of AM-treated STZ-diabetic rats. These data indicates that AM plays a role in protection of cardiac and renal dysfunction in hyperglycemic rats acting in part via cAMP and Akt-NO-cGMP signal transduction pathways.