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      Ivabradine Ameliorates Kidney Fibrosis in L-NAME-Induced Hypertension

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          Abstract

          Hypertension-induced renal injury is characterized by structural kidney alterations and function deterioration. Therapeutics for kidney protection are limited, thus novel renoprotectives in hypertension are being continuously sought out. Ivabradine, an inhibitor of the I f current in the sinoatrial node reducing heart rate (HR), was shown to be of benefit in various cardiovascular pathologies. Yet, data regarding potential renoprotection by ivabradine in hypertension are sparse. Thirty-six adult male Wistar rats were divided into non-diseased controls and rats with N G-nitro-L-arginine methyl ester (L-NAME)-induced hypertension to assess ivabradine's site-specific effect on kidney fibrosis. After 4 weeks of treatment, L-NAME increased the average systolic blood pressure (SBP) (by 27%), decreased glomerular density (by 28%) and increased glomerular tuft area (by 44%). Moreover, L-NAME induced glomerular, tubulointerstitial, and vascular/perivascular fibrosis by enhancing type I collagen volume (16-, 19- and 25-fold, respectively). L-NAME also increased the glomerular type IV collagen volume and the tubular injury score (3- and 8-fold, respectively). Ivabradine decreased average SBP and HR (by 8 and 12%, respectively), increased glomerular density (by 57%) and reduced glomerular tuft area (by 30%). Importantly, ivabradine decreased type I collagen volume at all three of the investigated sites (by 33, 38, and 72%, respectively) and enhanced vascular/perivascular type III collagen volume (by 67%). Furthermore, ivabradine decreased the glomerular type IV collagen volume and the tubular injury score (by 63 and 34%, respectively). We conclude that ivabradine attenuated the alterations of glomerular density and tuft area and modified renal fibrosis in a site-specific manner in L-NAME-hypertension. It is suggested that ivabradine may be renoprotective in hypertensive kidney disease.

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          Most cited references66

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          2018 ESC/ESH Guidelines for the management of arterial hypertension

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            The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?

            Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable versus progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, estimate its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technology, that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis.
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              Elevated blood pressures in mice lacking endothelial nitric oxide synthase.

              Nitric oxide produced in endothelial cells affects vascular tone. To investigate the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation, we have generated mice heterozygous (+/-) or homozygous (-/-) for disruption of the eNOS gene. Immunohistochemical staining with anti-eNOS antibodies showed reduced amounts of eNOS protein in +/- mice and absence of eNOS protein in -/- mutant mice. Male or female mice of all three eNOS genotypes were indistinguishable in general appearance and histology, except that -/- mice had lower body weights than +/+ or +/- mice. Blood pressures tended to be increased (by approximately 4 mmHg) in +/- mice compared with +/+, while -/- mice had a significant increase in pressure compared with +/+ mice (approximately 18 mmHg) or +/- mice (approximately 14 mmHg). Plasma renin concentration in the -/- mice was nearly twice that of +/+ mice, although kidney renin mRNA was modestly decreased in the -/- mice. Heart rates in the -/- mice were significantly lower than in +/- or +/+ mice. Appropriate genetic controls show that these phenotypes in F2 mice are due to the eNOS mutation and are not due to sequences that might differ between the two parental strains (129 and C57BL/6J) and are linked either to the eNOS locus or to an unlinked chromosomal region containing the renin locus. Thus eNOS is essential for maintenance of normal blood pressures and heart rates. Comparisons between the current eNOS mutant mice and previously generated inducible nitric oxide synthase mutants showed that homozygous mutants for the latter differ in having unaltered blood pressures and heart rates; both are susceptible to lipopolysaccharide-induced death.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                10 July 2020
                2020
                : 7
                : 325
                Affiliations
                [1] 1Institute of Pathophysiology, Faculty of Medicine, Comenius University , Bratislava, Slovakia
                [2] 2Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences , Bratislava, Slovakia
                [3] 3Institute of Pathological Anatomy, Faculty of Medicine, Comenius University , Bratislava, Slovakia
                [4] 4Department of Physiology, School of Medicine, Charles University , Prague, Czechia
                [5] 53rd Department of Internal Medicine, Faculty of Medicine, Comenius University , Bratislava, Slovakia
                [6] 6Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences , Bratislava, Slovakia
                Author notes

                Edited by: Jennifer Sullivan, Augusta University, United States

                Reviewed by: Hee-Seong Jang, University of Nebraska Medical Center, United States; Swastika Sur, University of California San Francisco, United States

                *Correspondence: Fedor Simko fedor.simko@ 123456fmed.uniba.sk

                This article was submitted to Nephrology, a section of the journal Frontiers in Medicine

                †These authors have contributed equally to this work

                Article
                10.3389/fmed.2020.00325
                7365878
                67868d26-e7c3-4c73-8c37-cf27d792ea64
                Copyright © 2020 Stanko, Baka, Repova, Aziriova, Krajcirovicova, Barta, Janega, Adamcova, Paulis and Simko.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 March 2020
                : 03 June 2020
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 71, Pages: 10, Words: 6556
                Funding
                Funded by: Vedecká Grantová Agentúra MŠVVaŠ SR a SAV 10.13039/501100006109
                Award ID: 1/0035/19
                Award ID: 2/0112/19
                Funded by: Univerzita Karlova v Praze 10.13039/100007397
                Award ID: PROGRES Q40/5
                Categories
                Medicine
                Brief Research Report

                ivabradine,l-name,hypertension,fibrosis,nephroprotection
                ivabradine, l-name, hypertension, fibrosis, nephroprotection

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