Jorge B. Cannata-Andía

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

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.

Chapter 79 – Vitamin D and Renal Disease

In chronic kidney disease (CKD), the progressive loss of renal capacity to maintain the functional integrity of the vitamin D endocrine system is a major determinant of the skeletal, renal, and cardiovascular damage that markedly increases mortality rates. This chapter updates the progress in our understanding of the pathophysiology underlying CKD-induced abnormalities in the systemic and local vitamin D bioactivation to its hormonal form, 1,25-dihydroxyvitamin D or calcitriol. Special focus is directed to the molecular bases to maximize the prosurvival actions of the calcitriol/vitamin D receptor complex in CKD beyond the suppression of the PTH gene and parathyroid cell growth including: (1) The attenuation of bone loss and vascular calcification unrelated to the control of secondary hyperparathyroidism; (2) The induction of the fibroblast growth factor 23 to prevent the proaging effects of hyperphosphatemia and of an excess of active vitamin D, and (3) The simultaneous induction of the klotho gene and inhibition of its two main downregulators, hypertension, and systemic inflammation to maintain the skeletal, renal, and cardiovascular protection conferred by renal and circulating klotho.

Mineral and Bone Disorders in Chronic Kidney Disease

The key players of the CKD–MBD are calcium, phosphorus, PTH, FGF23, and the vitamin D hormonal system. The progressive reduction of kidney function greatly modified the tightly interrelated mechanisms controlling these parameters. As a result, important changes occurred in the bone and mineral hormonal axis leading to changes in bone turnover with consequences in relevant clinical outcomes, such as decrease in bone mass with increased bone fragility and bone fractures and increased vascular and valvular calcification with great impact in the cardiovascular outcomes.