Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Abstract

In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-b, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-b, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

Preconditioning protects the heart in a prolonged uremic condition

“…Upregulation of renal renin-angiotensin-aldosterone system was also shown in rats with partial nephrectomy in our present study similarly to findings of other research groups (25,33,41). In our present study, increased plasma ANG II levels together with echocardiographic data suggest the development of a minimal left ventricular hypertrophy at week 30 in uremic animals.…”

“…Additionally, plasma ANG II level, which is an indirect marker of hypertension and left ventricular hypertrophy (20,27,28,43,58), was also higher in uremic rats. These results together with literature data (1,33,38,41) suggest the development of a minimal left ventricular hypertrophy in uremic animals at week 30 in our present study. In this model, we have found here that ischemic preconditioning is still effective in prolonged uremic condition.…”

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target. Adverse side-effects will likely be a challenging issue in the putative use of CaSR-modulating agents for the treatment of such a broad range of tissuespecific diseases; therefore, future studies should focus on the development of CaSR-modulating drugs with a higher selectivity for the CaSR and specificity for the tissue of interest.…”

“…During this process, loss of CaSR expression in vascular smooth muscle cells leads to the acquisition of an osteoblast-like phenotype and contributes to the generation of calcified nodules [119][120][121][122][123]. Koleganova and colleagues demonstrated, using an in vivo rat model for interstitial fibrosis and microvascular disease of the heart in uremia, that this transdifferentiation could be significantly delayed by administration of the calcimimetic R-568, suggesting the involvement of the CaSR in this process [124].…”

Left Ventricular Mass in Chronic Kidney Disease and ESRD

“…Vitamin D deficiency can activate the intracardiac RAS, and active vitamin D supplementation can cause regression of LVH and/or cardiac fibrosis (44). Lowering the greatly elevated parathyroid hormone (PTH) levels seen in experimental uremia by calcimimetics (cinacalcet) decreases cardiac fibrosis but does not affect LV mass (48). Calcitriol also reduces cardiac fibrosis and microvascular remodeling in experimental models of renal failure (50).…”