Ectonucleotidases in the kidney

Abstract

Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/ phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes' varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.

Cellular function and molecular structure of ecto-nucleotidases

“…They are found in essentially every mammalian tissue, including in a variety of tumors [459,460] and in serum [461]. They are often (but by far not exclusively) located at exchange surfaces such as the endothelium, the apical brush border of enterocytes, kidney tubules [462,463], the biliary epithelium, or the mucosal surface of airways [464]. They are also expressed a Human NPP1 residue numbering is used.…”

Purinergic signalling in the kidney in health and disease

“…The mechanism(s) of ATP exit from renal cells has/have not been defined. NDP nucleoside diphosphate, NTP nucleoside triphosphate (reproduced from [333], with permission from Springer) the vicinity of the P2 receptors in the cell membrane. Membrane-bound and soluble ectonucleotidases (vide infra) will rapidly metabolize secreted nucleotides, and it has been estimated that bulk-phase measurements could underestimate concentrations at the cell membrane by more than 20-fold, at least in astrocytes [179].…”

“…Four families of ectonucleotidases exist: ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatises, and all are found in the kidney [333]. These enzymes play an important part in renal nucleotide signalling.…”

“…NTPDase1 hydrolyses ATP and ADP with almost equal preference, whereas NTPDase2 has a much greater preference for ATP, therefore causing accumulation of ADP; NTPDases 3 and 8 are intermediate in their preference [333]. These differential preferences for hydrolysis are functionally significant.…”

Role of CD73 and extracellular adenosine in disease

“…CD39 null), this results in hepatic insulin resistance in murine models [11] and CD39 expression has been shown to correlate with fasting plasma glucose and haemoglobin A1C levels in humans. [12] Similarly, ENTPD-1 impacts diabetic nephropathy in murine models and functional polymorphisms of the gene also appear to influence renal outcomes in African Americans with diabetes [13][14][15].…”