Faculty Collaboration Database

Novel role of fumarate metabolism in dahl-salt sensitive hypertension. Hypertension 2009 Aug;54(2):255-60

Date

06/24/2009

Pubmed ID

19546378

Pubmed Central ID

PMC2721687

DOI

10.1161/HYPERTENSIONAHA.109.129528

Scopus ID

2-s2.0-68549122792 (requires institutional sign-in at Scopus site)   60 Citations

Abstract

In a previous proteomic study, we found dramatic differences in fumarase in the kidney between Dahl salt-sensitive rats and salt-insensitive consomic SS-13(BN) rats. Fumarase catalyzes the conversion between fumarate and l-malate in the tricarboxylic acid cycle. Little is known about the pathophysiological significance of fumarate metabolism in cardiovascular and renal functions, including salt-induced hypertension. The fumarase gene is located on the chromosome substituted in the SS-13(BN) rat. Sequencing of fumarase cDNA indicated the presence of lysine at amino acid position 481 in Dahl salt-sensitive rats and glutamic acid in Brown Norway and SS-13(BN) rats. Total fumarase activity was significantly lower in the kidneys of Dahl salt-sensitive rats compared with SS-13(BN) rats, despite an apparent compensatory increase in fumarase abundance in Dahl salt-sensitive rats. Intravenous infusion of a fumarate precursor in SS-13(BN) rats resulted in a fumarate excess in the renal medulla comparable to that seen in Dahl salt-sensitive rats. The infusion significantly exacerbated salt-induced hypertension in SS-13(BN) rats (140+/-3 vs125+/-2 mm Hg in vehicle control at day 5 on a 4% NaCl diet; P<0.05). In addition, the fumarate infusion increased renal medullary tissue levels of H2O2. Treatment of cultured human renal epithelial cells with the fumarate precursor also increased cellular levels of H2O2. These data suggest a novel role for fumarate metabolism in salt-induced hypertension and renal medullary oxidative stress.

Author List

Tian Z, Liu Y, Usa K, Mladinov D, Fang Y, Ding X, Greene AS, Cowley AW Jr, Liang M

Author

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin

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

Analysis of Variance
Animals
Biomarkers
Blotting, Western
DNA, Complementary
Disease Models, Animal
Fumarate Hydratase
Hypertension
Kidney Medulla
Kidney Tubules
Malates
Male
Oxidative Stress
Random Allocation
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Sodium Chloride, Dietary
Succinic Acid