Remodeling of Intramyocardial Arteries and Myocardium as a Target of Early Chronic Kidney Disease-Mineral and Bone Disorder: an Experimental Study

Introduction. Chronic kidney disease–mineral and bone disorder (CKD-MBD) plays a significant role in causing cardiovascular morbidity and mortality related to CKD. CKD-MBD has been studied during advanced stages when changes in inorganic phosphate (Pi) and its hormonal regulation are obvious. The initial phases of myocardial remodeling (MR) in early CKD-MBD remain poorly understood. Aim. To investigate the molecular and structural alterations in the myocardium and intramyocardial arteries in early-stage CKD-MBD model. Materials and methods. CKD-MBD was modeled using 3/4 nephrectomy in spontaneously hypertensive rats (SHR). Sham-operated rats served as a control. After 2 or 6 months, we assessed renal function, inorganic phosphate (Pi) metabolism, bone, myocardial and vascular histology and histomorphometry and gene profiles for Pi-dependent, pro-hypertrophic and pro-fibrotic signaling pathways in the myocardium. Results. The chronic kidney injury in the applied models corresponded to human CKD grade 1–2 and was accompanied by lower bone turnover with no increase in fibroblast growth factor 23 and parathyroid hormone levels. Myocardial remodeling was characterized by interstitial and perivascular fibrosis, thickening of the intramyocardial artery media, cardiomyocyte hypertrophy and tissue retention of phosphorus. The differences in the expression profiles included genes related to cell differentiation (Lgr4, Dkk1, Sfrp2) , vascularization (Jag1, Fzd2, Ptch1, Bmp4) and fibrosis (Hes1, Jag1, Mapk1/3, Ctnnb1), hypertrophy (Mapk1/3, Hes1, Jag1, Ctnnb1, Ppp3ca) and Pi balance (Ankh, Mapk1/3, Ppp3ca). Conclusion. The early stages of myocardial and vascular remodeling in CKD-MBD are associated with lower bone turnover and myocardial phosphorus accumulation concurrently with altered myocardial gene expression of pathways related to Pi metabolism, vascularization, fibrosis and hypertrophy.