Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis.

Abstract

BACKGROUND:

Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers.

METHODS:

Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated.

RESULTS:

Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters.

CONCLUSIONS:

VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

• Authors: Sara Panizo, Natalia Carrillo-López, Manuel Naves-Díaz, Guillermo Solache-Berrocal, Laura Martínez-Arias, Raúl R Rodrigues-Díez, Amalia Fernández-Vázquez, Carlos Martínez-Salgado, Marta Ruiz-Ortega, Adriana Dusso, Jorge B Cannata-Andía, Isabel Rodríguez
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 32 Issue 11 Pg. 1831-1840 (Nov 01 2017) ISSN: 1460-2385 [Electronic] England
• PMID: 28460073 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Biomarkers
• Collagen Type I
• Ergocalciferols
• MIRN29 microRNA, rat
• MIRN30 microRNA, rat
• MicroRNAs
• Receptors, Calcitriol
• Connective Tissue Growth Factor
• paricalcitol
• Matrix Metalloproteinase 2
• Mmp2 protein, rat
• Calcitriol

Topics

• Animals
• Biomarkers (metabolism)
• Calcitriol (pharmacology)
• Cardiomyopathies (etiology, metabolism)
• Collagen Type I (genetics, metabolism)
• Connective Tissue Growth Factor (genetics)
• Ergocalciferols (pharmacology)
• Fibrosis
• Gene Expression Regulation
• Kidney Failure, Chronic (complications, metabolism)
• Male
• Matrix Metalloproteinase 2 (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Myocardium (pathology)
• Rats
• Rats, Wistar
• Receptors, Calcitriol (physiology)
• Signal Transduction
• Uremia (complications, metabolism)