Vitamin D inhibits
renin expression and blocks the compensatory induction of
renin associated with the use of renin-angiotensin system inhibitors. Here we test the
therapeutic effects of two commonly used
vitamin D analogs and their combination with
losartan on the development of
left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle,
losartan,
paricalcitol,
doxercalciferol, a combination of
losartan and
paricalcitol, or a combination of
losartan and
doxercalciferol for 2 months. Blood pressure was markedly reduced by
losartan, but not by
paricalcitol or
doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with
losartan,
paricalcitol, or
doxercalciferol monotherapy and almost complete prevention of
left ventricular hypertrophy with the combination
therapies. Attenuation of cardiac and cardiomyocyte
hypertrophy, and suppression of atrial and brain
natriuretic peptides, were most marked in the combination
therapy groups. These changes were well correlated with left ventricular gene and
microRNA expression profiles in the different treatment groups. Renal and cardiac
renin expression was markedly increased in
losartan-treated animals, but nearly normalized with combination
therapy. The same
vitamin D analogs suppressed plasma
renin activity in patients receiving chronic
hemodialysis. These data demonstrate that
vitamin D analogs have potent antihypertrophic activity in part via suppression of
renin in the kidney and heart, and combination of these analogs with
losartan achieves much better
therapeutic effects because of the blockade of the compensatory
renin increase.