Novel role of fumarate metabolism in dahl-salt sensitive hypertension.
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.
Tian
Zhongmin
Z
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Liu
Yong
Y
Usa
Kristie
K
Mladinov
Domagoj
D
Fang
Yi
Y
Ding
Xiaoqiang
X
Greene
Andrew S
AS
Cowley
Allen W
AW
Liang
Mingyu
M
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018076:DNA, Complementary / Q000032:analysis; D004195:Disease Models, Animal; D005649:Fumarate Hydratase / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008293:Malates / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism*
D015415:Biomarkers; D018076:DNA, Complementary; D008293:Malates; D017673:Sodium Chloride, Dietary; C030298:malic acid; D019802:Succinic Acid; D005649:Fumarate Hydratase