Cardiac and Renal Effects of Atrasentan in Combination with Enalapril and Paricalcitol in Uremic Rats

Ritter, Cynthia S.; Zhang, Sarah; Finch, Jane; Liapis, Helen; Suarez, Edu; Ferder, León; Delmez, James A.; Slatopolsky, Eduardo

doi:10.1159/000355811

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…When the duration of treatment was only 20 weeks, the positive effects were not observed (Vaněčková et al 2012). This is consistent with a study in 5/6 nephrectomized female Sprague Dawley rats in which a three-month treatment with atrasentan in combination with enalapril (ACEi) and paricalcitol (vitamin D activator) had no additional renoprotective effects as compared to the treatment with enalapril alone (Ritter et al 2014). Unfortunately, beneficial effects were also not demonstrated in TGR rats in which the long-term treatment with ET A blockade on top of RAS blockade was delayed to the phase of established hypertension and CKD (Sedláková et al 2017).…”

Section: Endothelin Antagonists In Experimental Non-diabetic Ckdsupporting

confidence: 87%

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

Vaněčková

Hojná²,

Kadlecová³

et al. 2018

Physiol Res

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Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ETA) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ETA receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ETA blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ETA antagonists, at least under certain pathological conditions.

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Section: Endothelin Antagonists In Experimental Non-diabetic Ckdsupporting

confidence: 87%

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

Vaněčková

Hojná²,

Kadlecová³

et al. 2018

Physiol Res

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“…These findings are consistent with findings in uremic and/or hypertensive rat models. In these rats it was shown that an ETA receptor blocker reduces the size of myocytes in a blood pressure independent manner [42,43].…”

Section: Kidney Weight and Protein Excretionmentioning

confidence: 99%

Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice

Tsuprykov

Vignon-Zellweger

et al. 2016

Kidney Blood Press Res

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Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference: -2.57 mmHg, 95% CI: -4.98∼ -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95% CI: -10.76∼ -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure.

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“…Although some treatment studies in animal models of CKD show a reduction of cardiac hypertrophy without lowering blood pressure (41, 59, 176, 198, 209–211), thereby uncoupling cardiac injury from hypertension in the context of kidney injury, it is most likely that in CKD increases in blood pressure together with a variety of other factors, such as serum elevations of FGF23 and uremic toxins (212), synergistically contribute to cardiac injury. In fact, FGF23 might directly contribute to hypertension by targeting the renal renin-angiotensin system (205) and by regulating renal sodium handling via targeting the distal tubules (213).…”

Section: The Role Of Fgf23 In Uremic Cardiomyopathymentioning

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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Cardiac and Renal Effects of Atrasentan in Combination with Enalapril and Paricalcitol in Uremic Rats

Cited by 13 publications

References 39 publications

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice

Cardiac actions of fibroblast growth factor 23

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