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, 177 (2), 622-31

Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

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Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Juan Kong et al. Am J Pathol.

Abstract

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.

Figures

Figure 1
Figure 1
Effect of drug treatments on blood pressure. One-month old male SHRs were treated with vehicle (V), losartan (L, 30 mg/kg), paricalcitol (P, 400 ng/kg), doxercalciferol (D, 400 ng/kg), L+P or L+D for two months. Mean blood pressure was determined at the end of treatment. ∗∗∗P < 0.001 vs vehicle; n = 4.
Figure 2
Figure 2
Echocardiographic analysis of left ventricular wall thickness. Every SHR in the study was analyzed by echocardiography at the end of the treatment. A: Representative M-mode echocardiographs from V-, P- and L+P-treated SHRs. The position of anterior and posterior walls is marked. Similar images were seen in D- and L+D-treated rats. B and C: Thickness of anterior wall (B) and posterior wall (C) of the left ventricle at the end of the treatment. The wall thickness was calculated based on the echocardiographic data. The P values were for comparison with V, and between L+P or L+D and L, P or D. C, nonhypertensive WKY rats.
Figure 3
Figure 3
Heart morphology and histology. A: Heart weight to tibia length ratio in each treatment group of SHRs; B: H&E staining of cross-sections of the left ventricles from each group of SHRs; C: left ventricular cardiomyocytes stained with FITC-labeled wheat germ agglutinin; D: diameter of left ventricular cardiomyocytes. P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 vs V; ##P < 0.01 vs L, P or D.
Figure 4
Figure 4
Effect of the treatments on ANP and BNP levels. A: Northern blot analyses. Total RNAs were extracted from the left ventricle, and the blots were hybridized with 32P-labeled ANP or BNP cDNA probe. B: ANP and BNP mRNA levels quantified using a PhosphoImaging system; C: plasma ANP levels determined by ELISA. P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 vs V; ##P < 0.01 vs L, P or D.
Figure 5
Figure 5
Microarray analysis of gene expression profiles in the left ventricle. A: Number of genes down-regulated and up-regulated in each treatment group as indicated. B: Cluster analysis of the seven commonly regulated genes identified in all treatment groups as indicted. Red color: relatively high expression; Blue color: relatively low expression. C: Box plot showing the average value of the seven genes in each samples; D: Principal Component Analysis mapping showing the positional difference of each treatments in three-dimensional space.
Figure 6
Figure 6
Effect of the treatments on mir-208b levels in the left ventricle. TaqMan real-time PCR analyses confirm the down-regulation of mir-208b by all treatments as indicated. P < 0.05 vs V; n = 4.
Figure 7
Figure 7
Effect of the drug treatments on renin expression in the kidney and heart. A: Real-time RT-PCR analyses of renin mRNA transcript in the kidney of treatment groups as indicated; P < 0.05; ∗∗P < 0.01 vs V; ∗∗∗P < 0.01 vs L. B: Western blot analysis of renin protein levels, with relative fold changes shown at the bottom of the blot; C: immunostaining of kidney sections using anti-renin antibodies. Arrows indicate renin-expressing juxtaglomerular cells. D: RT-PCR determination of renin mRNA levels in the left ventricle of each treatment group as indicated, with relative fold changes shown at the bottom of the gel; E: immunostaining of left ventricular sections with anti-CD31 (upper panels, red) or anti-renin (lower panels, green) antibodies. Note that renin staining was mainly seen in the blood vessel walls.
Figure 8
Figure 8
Suppression of plasma renin activity by vitamin D therapy in hemodialysis patients. Plasma renin activity declined significantly between 14 and 90 days of dialysis in patients who received ≥30 days of active vitamin D therapy (n = 17, P < 0.01) but not in subjects who received no vitamin D analogs during this period (n = 11, P = 0.75). The difference in effect between treated and untreated patients was statistically significant (P = 0.025).

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