Fumarate and its downstream signalling pathways in the cardiorenal system: Recent insights and novel expositions in the etiology of hypertension

Hypertension, a risk factor for cardiorenal disease has a huge global health impact. Hence, there is a continuous search for new therapeutic targets and putative antihypertensive ligands. This search has transcended into the realm of mitochondrial metabolism which has been reported to underline the etiology of certain diseases, including hypertension. Recently, genetic alterations in the tricarboxylic acid (TCA) cycle enzyme, fumarase, which converts fumarate to malate, reportedly worsened salt-sensitive hypertension. These novel expositions shifted focus into the activity of TCA in the pathogenesis of hypertension. There is now evidence to show that a mechanistic link exists between blood pressure regulation and intermediaries in the TCA cycle involving fumarate metabolism. Fumarate has been reported to mediate the actions of endogenous ligands such as nitric oxide (NO), and hypoxia inducible factor (HIF)-1α. Similarly, there has been upregulation of protective genes such as nuclear erythroid factor 2 (Nrf2) and reduction in the expression of certain markers like kidney injury molecule 1 (KIM-1). There are reports of interactions with endogenous enzymes such as catalase (CAT) and renin via the activation of GPR91. Fumarate has also been shown to modulate the actions of renal ion channels and by extension, natriuresis. These actions of fumarate have conferred a reno- and cardio-protective effect in hypertension. This review evaluates the role of the TCA cycle, its mechanistic links, and significant contribution to blood pressure regulation with a view to understanding the possibility of a new pathological axis which may be involved in the pathogenesis of hypertension.