Paricalcitol Downregulates Myocardial Renin-Angiotensin and Fibroblast Growth Factor Expression and Attenuates Cardiac Hypertrophy in Uremic Rats

Autor: Yasmir Quiroz, Christian Faul, Bernardo Rodriguez-Iturbe, Michael Freundlich, Wacharee Seeherunvong, Y. C. Li, José R. Weisinger, Yanauri Bravo
Rok vydání: 2013
Předmět:
Zdroj: American Journal of Hypertension. 27:720-726
ISSN: 1941-7225
0895-7061
Popis: Left ventricular hypertrophy (LVH) is the most frequent cardiac complication of chronic kidney disease (CKD) and constitutes a powerful mortality risk factor.1,2 The pathogenesis of LVH is multifactorial and cannot account only for traditional risk factors such as hypertension and hypervolemia.2–4 Indeed, studies in experimental uremia have demonstrated that cardiac hypertrophy may develop independent of hypertension.5,6 Furthermore, disturbances of mineral metabolism may be involved, including hyperphosphatemia, increased parathyroid hormone, and fibroblast growth factor-23.7 While the cardiovascular system is not traditionally regarded as a target of 1,25(OH)2D3 (1,25D, calcitriol), this metabolite and its receptor the vitamin D receptor (VDR) have important effects on circulation8 and may play an important role in the development of LVH in uremia.9 In renal insufficiency, the decline in renal 1α-hydroxylase activity and the increased catabolic rate of 1,25D10 result in reduced circulating levels and 1,25D deficiency.11 The latter has been linked to increased cardiovascular mortality and can be reduced by treatment with the VDR agonists calcitriol or its less-calcemic analog paricalcitol [Pc; 19-nor-1,25(OH)2D2].12 Calcitriol therapy attenuates cardiac hypertrophy in experimental uremia and in patients on dialysis.13 A likely mechanism underlying the cardioprotective effects of vitamin D is the downregulation of the renin–angiotensin system (RAS) since VDR and 1α-hydroxylase knockout mice develop hyperreninemia and LVH,14,15 treatment with VDR activators improves cardiac hypertrophy in hypertensive rats,16 1,25D suppresses renin gene transcription,17 and Pc suppresses renal renin expression in normal mice.18 Several studies, including our own,8,19 have demonstrated that renin inhibition by Pc may offer a novel mechanism for suppressing the intrarenal RAS in various experimental and clinical conditions typically characterized by RAS upregulation. These observations raise the possibility that increased myocardial RAS activity plays a significant role in the development of cardiac hypertrophy in uremia and that VDR activators are capable of attenuating these changes. In support of this possibility, recent investigations have shown that myocardial RAS is regulated independently from the circulating RAS and plays a determinant role in the development of myocardial hypertrophy.20,21 All components of the RAS have been demonstrated in the myocardium of animals with intact renal function,21 and there is compelling evidence of the therapeutic effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) antagonists in experimental models of heart failure in animals with intact renal function.21 However, data on the mRNA expression of components of the RAS in the hearts of uremic animals are scarce, and the changes resulting from therapy with VDR activators or ACE inhibition in their myocardium have not been investigated. Fibroblast growth factor (FGF)-23, the 23rd member of the FGF family, is a potent negative regulator of circulating phosphate and 1,25D levels. Also, FGF-23 induces phosphaturia and lowers serum phosphorus through reduction of the sodium–phosphate cotransporters in the kidney proximal tubules and it directly suppresses renal 1α-hydroxylase, leading to decreased conversion of 25-hydroxyvitamin D to its active metabolite 1,25D.22 In addition, increasing evidence suggests intricate hormonal interactions between FGF-23, vitamin D, and the RAS, with important consequences for patients with CKD.23 Elevated circulating FGF-23 concentrations have been strongly associated with LVH and mortality risk in adults24 and, more recently, in children with CKD.25 Activation of FGF receptors (FGFRs), such as FGFR-1, has been implicated in the development of cardiac hypertrophy, and FGF-23 administration has resulted in LVH in animals and in hypertrophy of cardiomyocytes via FGFR-dependent signaling.26 However, the specific FGFR that mediates these effects has not been identified, and neither FGF-23 nor its obligatory coreceptor Klotho are expressed in cardiomyocytes.7,27 Therefore, a mechanistic explanation for the association between elevated FGF-23 levels and LVH remains elusive. These considerations prompted the present study in rats with cardiac hypertrophy associated with experimentally induced CKD. This study was designed to compare the effects of the VDR activator Pc with those of the ACE inhibitor enalapril (E) on uremic myocardial hypertrophy.
Databáze: OpenAIRE
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