Diabetes and hypertension: Pivotal involvement of purinergic signaling

Abstract

Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5'-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.

Keywords: ATP; Adenosine; Blood pressure; Ectonucleotidases; Glucose; Purinergic receptors.

Graphical abstract

Fig. 1

Overview of the purinergic signaling cascade. The purinergic pathway is comprised by several purine-hydrolyzing enzymes expressed on the cell surface, generally known as ectoenzymes, including E-NTPDase, E-NPP and E-5′-NT, that sequentially degrade nucleotides in a series of coordinated reactions. The resulting nucleoside adenosine (Ado) can be subsequently converted to inosine (Ino) by adenosine deaminase (ADA). Signaling molecules bind to ionotropic P2X receptors and metabotropic P2Y receptors depending on the affinity of each receptor for their nucleotide agonists. The four subtypes of P1 types have affinity to adenosine and are all G-protein-coupled receptors (GPCRs). The binding of the purinergic mediators to their specific receptors on the cell surface can turn on or off downstream signaling cascades leading to different cellular outcomes. Source: Authors artwork.

Fig. 2

ATP signaling in the purinergic system on insulin release. The purinergic system and its role in the release of insulin from pancreatic β cells is influenced by the signaling of the ATP molecule. Glucose is transported into the β cell via its GLUT-2 transporter to be metabolized. The ATP generated from pyruvate catabolism and other biomolecules is exported from the mitochondria to the cytosolic compartment. ATP promotes the closure of ATP-sensitive K + channels in the plasma membrane, resulting in cell depolarization, calcium influx (Ca^{2 +)} and consequent insulin release. In addition, stimulation of glucose-induced insulin secretion is also related to ATP release via pannexin 1 channels. Since ATP binds to purinergic receptors such as P2X₇R (stimulating increased levels of intracellular Ca^{2 +}), or P2Y₁R and P2Y₆R (either by activating second messengers such as cyclic adenosine 5′-monophosphate (cAMP), diacylglycerol (DAG) or by stimulating Ca^{2 +} secretion by the endoplasmic reticulum (ER) and consequent intracellular increase), this nucleotide leads to secretion of insulin-containing vesicles by β cells. In contrast, the activation of P2X₃R leads to inhibition of the secretion of this hormone. Source: Authors artwork.