Myocardial effects of VDR activators in renal failure

Abstract

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Traditional causes such as diabetes, smoking, aging and hypertension do not fully explain the high rate of morbidity from cardiovascular disease seen in these patients. The renin-angiotensin-aldosterone system (RAAS) regulates extracellular volume homeostasis, which contributes to blood pressure stability. Overactivity of this system is involved in the pathophysiology of cardio-renal disease. New evidence suggests that vitamin D receptor activators (VDRAs) have a suppressive effect on the RAAS; however, VDRAs also have anti-inflammatory and anti-fibrotic effects. We have demonstrated that paricalcitol, a VDRA, ameliorates left ventricular hypertrophy (LVH) in uremic rats by up-regulating the VDR, decreasing myocardial PCNA and also decreasing myocardial oxidative stress. Thus, paricalcitol can suppress the progression of LVH, myocardial and perivascular fibrosis and myocardial arterial vessel thickness presumably by up-regulating the VDR. Paricalcitol may prove to have a substantial beneficial effect on cardiac disease and its outcome in patients with CKD. Prospective randomized studies in CKD patients are necessary to confirm these results.

Fig.1

After four weeks of uremia, left ventricular weight significantly increased compared to normal rats, but treatment with paricalcitol 3 times per week for four weeks, minimized left ventricular hypertrophy.

Fig.2

Western blot analysis shows that, compared to normal rats, 4 weeks of uremia causes a decrease in VDR expression in the myocardium.

Fig.3

Immunohistochemistry confirmed the decrease in VDR expression in myocardium after 4 weeks of uremia (UC). Treatment with paricalcitol from the onset of uremia, for 4 weeks, prevented this decrease in VDR expression

Fig. 4

The quantification of the VDR in the myocardium is represented in this figure. VDR expression decreased from 774 ± 58 positive cells/1000 cells in normal animals to 362 ± 45 positive cells/1000 cells(p<0.01) after 4 weeks of uremia (UC). Treatment with paricalcitol from the onset of uremia, prevented the decrease in VDR expression (775 ± 52 positive cells/1000 cells, (p<0.01).

Fig. 5

Immunohistochemistry analysis shows that compared to normal rats, 4 weeks of uremia increased PCNA expression, while treatment with paricalcitol abolished this increase.

Fig. 6

Shows the quantification of PCNA positive cells. PCNA positive cells increased from 81 ± 21 cells/1000 cells in normal rats to 299 ± 69 cells /1000 cells (p<0.01). Paricalcitol treatment abolished this increase (82 ± 6 cells/ 1000 cells, p<0.01).

Fig. 7

Interstitial fibrosis was assessed using a Masson trichrome stain. Compared to normal rats, 4 weeks of uremia produced marked interstitial fibrosis in the myocardium. Myocardium from rats treated with paricalcitol, from the onset of uremia, displayed virtually no interstitial fibrosis.

Fig.8

Perivascular fibrosis was also assessed using a Masson trichrome stain. Compared to normal rats, 4 weeks of uremia produced significant areas of perivascular fibrosis well as increased vessel thickness in the myocardium from these rats. Treatment with paricalcitol, from the onset of uremia, markedly reduced the development of perivascular fibrosis and the increase in the vessel thickness.