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      Elevation of fumarase attenuates hypertension and can result from a nonsynonymous sequence variation or increased expression depending on rat strain

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          Abstract

          The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13 BN rats. SS.13 BN rats have a Brown Norway (BN) allele of fumarase and exhibit attenuated hypertension. The SS allele of fumarase differs from the BN allele by a K481E sequence variation. It remains unknown whether higher fumarase activities can attenuate hypertension and whether the mechanism is relevant without the K481E variation. We developed SS-TgFh1 transgenic rats overexpressing fumarase on the background of the SS rat. Hypertension was attenuated in SS-TgFh1 rats. Mean arterial pressure in SS-TgFh1 rats was 20 mmHg lower than transgene-negative SS littermates after 12 days on a 4% NaCl diet. Fumarase overexpression decreased H 2O 2, while fumarase knockdown increased H 2O 2. Ectopically expressed BN form of fumarase had higher specific activity than the SS form. However, sequencing of more than a dozen rat strains indicated most rat strains including salt-insensitive Sprague-Dawley (SD) rats had the SS allele of fumarase. Despite that, total fumarase enzyme activity in the renal medulla was still higher in SD rats than in SS rats, which was associated with higher expression of fumarase in SD. H 2O 2 can suppress the expression of fumarase. Renal medullary interstitial administration of fumarase siRNA in SD rats resulted in higher blood pressure on the high-salt diet. These findings indicate elevation of total fumarase activity attenuates the development of hypertension and can result from a nonsynonymous sequence variation in some rat strains and higher expression in other rat strains.

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          Author and article information

          Journal
          Physiol Genomics
          Physiol. Genomics
          physiolgenomics
          physiolgenomics
          PHYSIOLGENOMICS
          Physiological Genomics
          American Physiological Society (Bethesda, MD )
          1094-8341
          1531-2267
          1 September 2017
          28 July 2017
          1 September 2018
          : 49
          : 9
          : 496-504
          Affiliations
          [1] 1Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin , Milwaukee, Wisconsin;
          [2] 2Human and Molecular Genetics Center, Medical College of Wisconsin , Milwaukee, Wisconsin;
          [3] 3Department of Nephrology, Shenzhen Second People's Hospital and the First Affiliated Hospital of Shenzhen University , Shenzhen, China; and
          [4] 4The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University , Xi’an, China
          Author notes
          [*]

          K. Usa and Y. Liu contributed equally to this work; Z. Tian and M. Liang are cosenior authors of this work.

          Address for reprint requests and other correspondence: M. Liang, Medical College of Wisconsin, Physiology and Center of Systems Molecular Medicine, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: mliang@ 123456mcw.edu ).
          Article
          PMC5625267 PMC5625267 5625267 PG-00063-2017 PG-00063-2017
          10.1152/physiolgenomics.00063.2017
          5625267
          28754823
          96fc9a0b-9b2a-4355-9158-98f2b70da3a7
          Copyright © 2017 the American Physiological Society
          History
          : 11 July 2017
          : 25 July 2017
          : 25 July 2017
          Funding
          Funded by: http://doi.org/10.13039/100000050 HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)
          Award ID: HL-116264-7861
          Categories
          Research Article
          General Interest

          hypertension,metabolism,fumarase,kidney,genetics
          hypertension, metabolism, fumarase, kidney, genetics

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