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

Freundlich, Michael; Li, Yan C.; Quiroz, Yasmir; Bravo, Yanauri; Seeherunvong, Wacharee; Faul, Christian; Weisinger, José R.; Rodríguez‐Iturbe, Bernardo

doi:10.1093/ajh/hpt177

Cited by 46 publications

(40 citation statements)

References 39 publications

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“…Furthermore, in a Zebrafish model of cardiac regeneration following myocardial ablation, expression levels of FGFR2 and FGFR4 are increased (57). Finally, in cardiac hypertrophy associated with kidney injury (also called uremic cardiomyopathy and discussed in more detail below), cardiac FGFR4 and FGFR1 levels are significantly elevated in patients (42) and rat models (58), respectively. In this scenario, FGFR4 activation and subsequent PLCγ/calcineurin/NFAT signaling seems to promote cardiac hypertrophy (41, 59).…”

Section: The Role Of Fibroblast Growth Factor Receptors In the Heartmentioning

confidence: 99%

Cardiac actions of fibroblast growth factor 23

Faul

2017

Bone

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Fibroblast growth factors (FGF) are mitogenic signal mediators that induce cell proliferation and survival. Although cardiac myocytes are post-mitotic, they have been shown to be able to respond to local and circulating FGFs. While precise molecular mechanisms are not well characterized, some FGF family members have been shown to induce cardiac remodeling under physiologic conditions by mediating hypertrophic growth in cardiac myocytes and by promoting angiogenesis, both events leading to increased cardiac function and output. This FGF-mediated physiologic scenario might transition into a pathologic situation involving cardiac cell death, fibrosis and inflammation, and eventually cardiac dysfunction and heart failure. As discussed here, cardiac actions of FGFs - with the majority of studies focusing on FGF2, FGF21 and FGF23 - and their specific FGF receptors (FGFR) and precise target cell types within the heart, are currently under experimental investigation. Especially cardiac effects of endocrine FGFs entered center stage over the past five years, as they might provide communication routes that couple metabolic mechanisms, such as bone-regulated phosphate homeostasis, or metabolic stress, such as hyperphosphatemia associated with kidney injury, with changes in cardiac structure and function. In this context, it has been shown that elevated serum FGF23 can directly tackle cardiac myocytes via FGFR4 thereby contributing to cardiac hypertrophy in models of chronic kidney disease, also called uremic cardiomyopathy. Precise characterization of FGFs and their origin and regulation of expression, and even more importantly, the identification of the FGFR isoforms that mediate their cardiac actions should help to develop novel pharmacological interventions for heart failure, such as FGFR4 inhibition to tackle uremic cardiomyopathy.

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Section: The Role Of Fibroblast Growth Factor Receptors In the Heartmentioning

confidence: 99%

Cardiac actions of fibroblast growth factor 23

Faul

2017

Bone

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“…In addition, 1,25(OH) 2 D 3 downregulates AT 1 R expression in both cultured adipocytes (294) and renal arteries from hypertensive patients (114). Very recently, paricalcitol (a vitamin D analog) downregulated the myocardial renin, angiotensinogen, and fibroblast growth factor receptor-1 expressions in rats that were made uremic by 5/6 nephrectomy (143).…”

Section: The Klotho-vitamin D-ras Connectionmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…Animal studies (mice) have shown that the 1,25(OH) 2 D-VDR complex negatively regulates renin expression, and that this vitamin D-induced reduction in RAAS activity can prevent adverse vascular outcomes to a similar extent induced by pharmacologic angiotensin-receptor antagonism(15, 87-93). Human studies have supported this theory, demonstrating that low circulating vitamin D concentrations are associated with higher plasma renin activity and angiotensin II concentrations(86, 94, 95), and that vitamin D deficiency is associated with higher RAAS activity that can be lowered following intervention with vitamin D 3 therapy(72, 94, 96).…”

Section: Introductionmentioning

confidence: 99%

The renin–angiotensin–aldosterone system and calcium-regulatory hormones

2015

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There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact in order to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies, and provide insight into the results of prior and on-going intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

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

Abstract: Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs.

Cited by 46 publications

References 39 publications

Cardiac actions of fibroblast growth factor 23

Cardiac actions of fibroblast growth factor 23

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

The renin–angiotensin–aldosterone system and calcium-regulatory hormones

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