Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals.

Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)(2)D(2)), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS+PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS+PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials.

Mechanistic analysis of VDR-mediated renin suppression.

BACKGROUND: The vitamin D receptor (VDR) is involved in the regulation of renin expression and vitamin D analogs down-regulated renin mRNA expression in As4.1 cells. METHODS: Microarray analysis was used to assess the VDR-mediated gene expression profile in As4.1 cells treated with paricalcitol, followed by real-time RT-PCR. Mechanistic analyses were done using siRNA, electrophoretic mobility shift assay (EMSA) and Western blotting. RESULTS: Microarray analysis shows that 709 target genes were affected by paricalcitol with 286 up- and 423 downregulated. A number of major pathways were impacted including transcription factors. Real-time RT-PCR confirmed the microarray results. Treatment of the cells with siRNA against nuclear receptor co-repressor (NCOR1) eliminated VDR-mediated renin suppression. Using EMSA, paricalcitol treatment reduced the level of protein complex binding to the cyclic AMP-responsive element (CRE)-like domain in the renin distal enhancer region. VDR, CRE-binding protein (CREB1) and NCOR1 were identified in the complex binding to the CRE-like domain by Western blot in the paricalcitol-treated cells. Paricalcitol treatment resulted in an increase in the VDR level, but no significant change in the CREB1 and NCOR1 levels. CONCLUSION: These results suggest that VDR-mediated renin suppression likely acts through a transcriptional regulatory complex including CREB1, NCOR1 and VDR that binds to the CRE-like domain in the renin enhancer region.