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

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...

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Published in:Nephrology, dialysis, transplantation dialysis, transplantation, 2017-11, Vol.32 (11), p.1831-1840
Main Authors: Panizo, Sara, Carrillo-López, Natalia, Naves-Díaz, Manuel, Solache-Berrocal, Guillermo, Martínez-Arias, Laura, Rodrigues-Díez, Raúl R, Fernández-Vázquez, Amalia, Martínez-Salgado, Carlos, Ruiz-Ortega, Marta, Dusso, Adriana, Cannata-Andía, Jorge B, Rodríguez, Isabel
Format: Article
Language:English
Subjects:
Animals
Biomarkers - metabolism
Calcitriol - pharmacology
Cardiomyopathies - etiology
Cardiomyopathies - metabolism
Collagen Type I - genetics
Collagen Type I - metabolism
Connective Tissue Growth Factor - genetics
Ergocalciferols - pharmacology
Fibrosis
Gene Expression Regulation
Kidney Failure, Chronic - complications
Kidney Failure, Chronic - metabolism
Male
Matrix Metalloproteinase 2 - genetics
Matrix Metalloproteinase 2 - metabolism
MicroRNAs - genetics
MicroRNAs - metabolism
Myocardium - pathology
Rats
Rats, Wistar
Receptors, Calcitriol - physiology
Signal Transduction
Uremia - complications
Uremia - metabolism
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Summary: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. 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. 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. 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.
ISSN:0931-0509
1460-2385
DOI:10.1093/ndt/gfx060