Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Kong, Juan; Kim, Gene; Wei, Minjie; Sun, Tao; Li, George; Liu, Shu Q.; Li, Xinmin; Bhan, Ishir; Zhao, Qun; Thadhani, Ravi; Li, Yan Chun

doi:10.2353/ajpath.2010.091292

Cited by 95 publications

(75 citation statements)

References 48 publications

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“…Furthermore, the antihypertrophic activity of VDR activators/ agonists has been demonstrated by several studies in rodent models of cardiac hypertrophy. Thus paricalcitol and 1,25(OH) 2 D 3 have been shown to reverse or prevent the hypertrophic phenotype in various models of experimental hypertension such as Dahl S rats (10), spontaneously hypertensive rats (18), and heart failure-prone spontaneously hypertensive rats (23). In addition, this protective effect was also observed in the 5/6 nephrectomy rodent, a model of chronic renal failure (26).…”

Section: Discussionmentioning

confidence: 94%

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

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-Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 g/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H 2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies. diabetic nephropathy; renin-angiotensin system; angiotensin-converting enzyme 2; animal model DIABETIC NEPHROPATHY IS THE leading cause of end-stage renal disease in the developed world (34). Previous studies have suggested that the renin-angiotensin system (RAS) is a major mediator of progressive renal injury in diabetic nephropathy. Drugs that target the RAS, including angiotensin-converting enzyme inhibitors and ANG II type 1 receptor blockers, have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (1, 4, 6, 21, 31). The systemic components of the RAS are altered in diabetes mellitus (32) and the intrarenal RAS is thought to play the major damaging role (25). The angiotensin-converting enzyme 2 (ACE2) has been identified in humans and differs from angiotensin-converting enzyme (ACE) in that it preferentially removes carboxy-terminal hydrophobic or basic amino acids (5, 12). Whereas ACE forms ANG II from ANG I, ACE2 is a major route of ANG II metabolism to ANG 1-7 (5, 39). ...

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Section: Discussionmentioning

confidence: 94%

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

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“…The long-term consequence of this increase with respect to cardiovascular risk has not been explored, but strong evidence relating higher FGF23 with worse outcome possibly cautions against excessive active vitamin D use. Indeed, although observational studies of hemodialysis patients suggest a survival advantage with active vitamin D therapy (111) (albeit attenuated at high doses) (112) and studies in non-CKD animal models attest to the protective properties of vitamin D receptor agonists (VDRAs) on cardiac hypertrophy (113,114), recent randomized controlled trials in CKD patients have failed to show any improvement in left ventricular structure or function with paracalcitol versus placebo (115,116). Thus, in the setting of CKD, the benefit of VDRAs on the heart seems uncertain.…”

Section: Vitamin Dmentioning

confidence: 99%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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“…These mice develop elevated BPs and left ventricular hypertrophy (18), which occurs due to a rise in renin consequent to loss of normal suppression of the renin-angiotensin system by vitamin D (19). In rats with spontaneous hypertension, treatment with vitamin D analogs ameliorates left ventricular hypertrophy and improves left ventricular diastolic measures (20). Active vitamin D, in various forms, decreases albuminuria in multiple animal models of kidney disease, including Heymann nephritis (21), murine MRL/l lupus nephritis (22), mercuric-chloride-induced nephrotic syndrome (23), and subtotal nephrectomized rats (24).…”

Section: Effects Of Vitamin D and Its Analogs In Animal Modelsmentioning

confidence: 99%

Vitamin D Therapy in Chronic Kidney Disease and End Stage Renal Disease

Melamed

Thadhani

2012

Clinical Journal of the American Society of Nephrology

106

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SummaryVitamin D has garnered much research and debate about supplementation in recent years, not only as it pertains to patients with kidney disease but also to those in the general population. This review discusses observational and available clinical trial evidence about the effects of both calcitriol and vitamin D analogs (active) and ergocalciferol and cholecalciferol (nutritional) vitamin D in patients with CKD and ESRD.

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Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Cited by 95 publications

References 48 publications

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Vitamin D Therapy in Chronic Kidney Disease and End Stage Renal Disease

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