Malate and Aspartate Increase L-Arginine and Nitric Oxide and Attenuate Hypertension

Abstract

Fumarase catalyzes the interconversion of fumarate and L-malate in the tricarboxylic acid cycle. The Dahl salt-sensitive (SS) rat, a model of salt-sensitive hypertension, exhibits fumarase insufficiencies. To investigate the mechanism mediating the effect of fumarase-related metabolites on hypertension, we considered the pathway in which L-malate can be converted to oxaloacetate, aspartate, argininosuccinate, and L-arginine, the substrate of nitric oxide (NO) synthase. The levels of aspartate, citrulline, L-arginine, and NO were significantly decreased in the kidneys of SS rats compared to salt-insensitive consomic SS.13 rats. Knockdown of fumarase in human kidney cells and vascular endothelial cells resulted in decreased levels of malate, aspartate, L-arginine, and NO. Supplementation of aspartate or malate increased renal levels of L-arginine and NO and attenuated hypertension in SS rats. These findings reveal a multi-step metabolic pathway important for hypertension in which malate and aspartate may modulate blood pressure by altering levels of L-arginine and NO.

MicroRNA-214-3p in the Kidney Contributes to the Development of Hypertension

“…NO levels are reduced in the kidneys of SS rats. 54 The NO substrate L-arginine, given either systemically or locally in the renal medulla, as well as other approaches that elevate NO levels, has potent effects in attenuating hypertension in SS rats. [54][55][56] Previous studies from our laboratory have shown broad expression of miR-214-3p in glomeruli, tubules, and vascular cells, many of which are known to express eNOS.…”

“…54 The NO substrate L-arginine, given either systemically or locally in the renal medulla, as well as other approaches that elevate NO levels, has potent effects in attenuating hypertension in SS rats. [54][55][56] Previous studies from our laboratory have shown broad expression of miR-214-3p in glomeruli, tubules, and vascular cells, many of which are known to express eNOS. 12,13,19 Importantly, miR-214-3p directly targets eNOS, and the antihypertensive effect of miR-214-3p inhibition was lost in SS-Nos3 +/2 rats, suggesting that it requires an intact capacity of eNOS expression.…”

Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet

“… 19 Metabolic deficiencies exist in SS rats and appear to contribute to salt-induced hypertension. 11 - 13 , 31 , 32 It remains to be determined whether the effect of BAIBA on salt-induced hypertension is mediated by metabolic or other effects of BAIBA.…”

“… 13 , 37 Malate attenuates hypertension in SS rats via a novel malate-aspartate-arginine-NO pathway that we recently discovered. 32 Citrulline is produced when arginine is used by nitric oxide synthases to generate nitric oxide, a potent regulator of blood pressure. Citrulline can, in turn, be used to re-generate arginine.…”

Combined metabolomic and correlation networks analyses reveal fumarase insufficiency altered amino acid metabolism

“…The results of these research suggest that the source of the protein in the diet, in particular the amino acid composition of protein in the diet, has a significant impact on the levels of blood pressure and renal disease in the SS rats. Recent studies by our group indicated that fumarase insufficiency was associated with decreased levels of aspartate, glycine, citrulline and nitric oxide (NO) in SS rats and human umbilical vein endothelial cells (HUVEC) (Hou et al, ). NO is a potent anti‐hypertensive agent.…”