Regulation of Vascular and Renal Function by Metabolite Receptors

Abstract

To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis—from salt and water balance to metabolism—by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families—(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and (c) short-chain fatty acid receptors—we emphasize the unique and important roles that these receptors play in renal and vascular physiology and pathophysiology.

Endothelial Cell Autophagy Maintains Shear Stress–Induced Nitric Oxide Generation via Glycolysis-Dependent Purinergic Signaling to Endothelial Nitric Oxide Synthase

“…28, 29 As would be predicted from cellular ATP results shown in Fig 2C, 2E, and 2G, shear-induced extracellular ATP accumulation was : robust in ECs transfected with scrambled but not Atg3 siRNA (Fig 3A); prevented in control ECs transfected with GLUT1 siRNA (Fig 3B); and restored by GLUT1 overexpression in ECs with compromised autophagy (Fig 3C). …”

“…Extracellular nucleotides have important biological roles as signaling molecules that regulate cellular functions under physiological and pathophysiological conditions reviewed in 29 . eNOS is regulated at multiple levels 39–42 , including via nucleotide activation of purinergic receptors.…”

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…Prescient ex vivo studies using pressure myography applied to rodent and human samples suggested that SCFA induce the vasodilation of resistance vessels in an endothelium-dependent manner [53][54][55]. Binding of SCFAs to the GPCR can activate a variety of intracellular signaling cascades, involving nuclear transcription, enzyme activation, and cell membrane ion transport [56]. Interestingly enough, sensory GPCR have been identified in tissues and organs not directly linked to taste or olfaction, like the kidney and the cardiovascular system [51,[57][58][59].…”

“…with no identified endogenous ligands and functions. Still, olfactory receptor 78 (Olfr78) and Gpr41 have been recently demonstrated to act as receptors for SCFAs, with a putative role in BP control [56,60,61]. Of note, 2 additional SCFA GPCR are currently under investigation: Gpr109A (butyrate) and Gpr43 (acetate, propionate, and butyrate) [56].…”

A place for host–microbe symbiosis in the comparative physiologist's toolbox

“…1). Bacterial metabolites can affect renal and cardiovascular systems (Peti-Peterdi et al, 2016), musculoskeletal (Charles et al, 2015) and neuroendocrine function (Neuman et al, 2015;Yano et al, 2015), adipose tissue (Velagapudi et al, 2010), and cellular and whole-body metabolism (Bauer et al, 2016;Mika and Fleshner, 2016;Wong et al, 2014). Liver-derived bile acids within the gut lumen are modified by bacterial enzymes, which alters their rates of absorption into the systemic circulation.…”