Role of adenosine 5'-triphosphate in regulating renal microvascular function and in hypertension

Abstract

ATP is an essential energy substrate for cellular metabolism, but it can also influence many biological processes when released into the extracellular milieu. Research has established that extracellular ATP acts as an autocrine/paracrine factor that regulates many physiological functions. Alternatively, excessive extracellular ATP levels contribute to pathophysiological processes, such as inflammation, cell proliferation and apoptosis, and atherosclerosis. Renal P2 receptors are widely distributed throughout glomeruli, vasculature, and tubular segments and participate in controlling renal vascular resistance, mediating renal autoregulation, and regulating tubular transport function. This review will focus on the role of ATP-P2 receptor signaling in regulating renal microvascular function and autoregulation, recent advances on the role of ATP-P2 signaling in hypertension-associated renal vascular injury, and emerging new directions.

Figure 1

Schematic diagram illustrating the catabolic pathways for degrading ATP to form ADP, AMP and adenosine by a series ecto-nucleotidases (NTPDases: nucleotide triphosphate diphosphohydrolases; NPPs: ecto-nucleotide pyrophosphatase; ecto-5’-NT: ecto-5'-nucleotidases, and ALP: ecto-alkaline phosphatases). ATP, its metabolites and its associated intracellular signaling pathways. The signaling pathways depicted for P1 receptor activation reflect conventionally held mechanisms.

Figure 2

Schematic diagram representing the postulated TGF mechanism in juxtaglomerular region. Increased luminal [NaCl] delivery stimulates Na-K-2Cl which leads to ATP release from the basolateral membrane of macula densa cells via maxi anion channels. ATP vasoconstricts afferent arterioles via activating P2X₁ receptors and/or adenosine (ado) converted from ATP by ecto-nucleotide pyrophosphatase (NPPs), ectonucleoside triphosphate diphosphohydrolases (NTPD), and ecto-5'-nucleotidases (ecto-5’-NT), respectively, vasoconstricts afferent arterioles via activating A₁ receptors.