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Elevation of fumarase attenuates hypertension and can result from a nonsynonymous sequence variation or increased expression depending on rat strain. Physiol Genomics 2017 Sep 01;49(9):496-504

Date

07/30/2017

Pubmed ID

28754823

Pubmed Central ID

PMC5625267

DOI

10.1152/physiolgenomics.00063.2017

Scopus ID

2-s2.0-85029592375   7 Citations

Abstract

The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13 rats. SS.13 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 HO, while fumarase knockdown increased HO 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. HO 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.

Author List

Usa K, Liu Y, Geurts AM, Cheng Y, Lazar J, Baker MA, Grzybowski M, He Y, Tian Z, Liang M

Authors

Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Mingyu Liang PhD Center Director, Professor in the Physiology department at Medical College of Wisconsin
Yong Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Fumarate Hydratase
Genetic Variation
HEK293 Cells
Humans
Hydrogen Peroxide
Hypertension
Oxidative Stress
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Rats, Sprague-Dawley
Rats, Transgenic
Sequence Analysis, DNA
Up-Regulation
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc