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      Hydrogen Sulfide Protects Hyperhomocysteinemia-Induced Renal Damage by Modulation of Caveolin and eNOS Interaction

      1 , 2 , , 1

      Scientific Reports

      Nature Publishing Group UK

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          Abstract

          The accumulation of homocysteine (Hcy) during chronic kidney failure (CKD) can exert toxic effects on the glomeruli and tubulo-interstitial region. Among the potential mechanisms, the formation of highly reactive metabolite, Hcy thiolactone, is known to modify proteins by N-homocysteinylation, leading to protein degradation, stress and impaired function. Previous studies documented impaired nitric oxide production and altered caveolin expression in hyperhomocysteinemia (HHcy), leading to endothelial dysfunction. The aim of this study was to determine whether Hhcy homocysteinylates endothelial nitric oxide synthase (eNOS) and alters caveolin-1 expression to decrease nitric oxide bioavailability, causing hypertension and renal dysfunction. We also examined whether hydrogen sulfide (H 2S) could dehomocysteinylate eNOS to protect the kidney. WT and Cystathionine β-Synthase deficient (CBS+/−) mice representing HHcy were treated without or with sodium hydrogen sulfide (NaHS), a H 2S donor (30 µM), in drinking water for 8 weeks. Hhcy mice (CBS+/−) showed low levels of plasma H 2S, elevated systolic blood pressure (SBP) and renal dysfunction. H 2S treatment reduced SBP and improved renal function. Hhcy was associated with homocysteinylation of eNOS, reduced enzyme activity and upregulation of caveolin-1 expression. Further, Hhcy increased extracellular matrix (ECM) protein deposition and disruption of gap junction proteins, connexins. H 2S treatment reversed the changes above and transfection of triple genes producing H 2S (CBS, CSE and 3MST) showed reduction of vascular smooth muscle cell proliferation. We conclude that during Hhcy, homocysteinylation of eNOS and disruption of caveolin-mediated regulation leads to ECM remodeling and hypertension, and H 2S treatment attenuates renovascular damage.

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          Most cited references 67

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          H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

          Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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            The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

            Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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              Caveolae: from cell biology to animal physiology.

              Among the membrane compartments of a cell, vesicles known as "caveolae" have long defied functional characterization. However, since the identification of a family of proteins termed "caveolins", that form and reside in caveolae, a better understanding has emerged. It is now clear that caveolae do not merely play a singular role in the cell, but are pleiotropic in nature-serving to modulate many cellular functions. The purpose of this review is to explicate what is known about caveolins/caveolae and highlight growing areas of caveolar research.
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                Author and article information

                Contributors
                utpal.sen@louisville.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                18 February 2019
                18 February 2019
                2019
                : 9
                Affiliations
                [1 ]ISNI 0000 0001 2113 1622, GRID grid.266623.5, Department of Physiology, , School of Medicine, University of Louisville, ; Louisville, KY 40292 USA
                [2 ]ISNI 0000 0004 1768 519X, GRID grid.419478.7, Department of Botany, , West Bengal State University, Berunanpukuria, ; Kolkata, West Bengal PIN 700126 India
                Article
                38467
                10.1038/s41598-018-38467-6
                6379383
                30778103
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000050, U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI);
                Award ID: HL104103
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);
                Award ID: DK 104653
                Award Recipient :
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