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(Hypertension. 2009;54:255.)
© 2009 American Heart Association, Inc.

Original Articles

Novel Role of Fumarate Metabolism in Dahl-Salt Sensitive Hypertension

Zhongmin Tian; Yong Liu; Kristie Usa; Domagoj Mladinov; Yi Fang; Xiaoqiang Ding; Andrew S. Greene; Allen W. Cowley, Jr; Mingyu Liang

From the Department of Physiology (Z.T., Y.L., K.U., D.M., Y.F., A.S.G., A.W.C., M.L.) and Biotechnology and Biomedical Engineering Center (Z.T., A.S.G.), Medical College of Wisconsin, Milwaukee; Department of Biomedical Engineering (Z.T.), Xi'an Jiaotong University, Shanxi, People’s Republic of China; and the Department of Nephrology (Y.F., X.D.), Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China.

Correspondence to Mingyu Liang, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226. E-mail mliang{at}mcw.edu

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.

Key Words: hypertension • gene • tricarboxylic acid cycle • kidney • oxidative stress • rat