Uncontrolled inflammation is one of the leading causes of kidney failure.

Uncontrolled inflammation is one of the leading causes of kidney failure. detectors mediators and effectors of swelling in the kidney via P2Y14. Introduction Kidney failure is almost usually associated with uncontrolled swelling [1 2 A link between renal swelling and signaling via purinergic receptors has been established but very little is currently known concerning the underlying mechanisms involved and how to prevent and alleviate the severe damage cause by swelling. Several purinergic receptors are indicated in the kidney and deregulation of purinergic signaling is definitely associated with several pathologies including hypertension chronic kidney disease acute kidney injury diabetic nephropathy and glomerulonephritis [3 4 Purinergic receptors are involved in the rules of water electrolyte and volume homeostasis by collecting duct principal cells [5-8]. However there is limited knowledge within the purinergic rules of the other major cell type of the collecting duct the intercalated cell (IC). ICs participate in the maintenance of acid/foundation homeostasis via the proton-pumping V-ATPase [9 10 In the epididymis ATP and adenosine are potent activators of V-ATPase-dependent proton secretion in obvious cells which are analogous to ICs [11]. Extracellular ATP NNC 55-0396 stimulates bone resorption in osteoclasts a process that also requires activity of the V-ATPase [12 13 These studies suggest a role for the purinergic Tm6sf1 rules of acid/base transport in NNC 55-0396 the kidney but the purinergic receptor signature of ICs still remains to be NNC 55-0396 characterized. Nucleotide-activated purinergic receptors are separated into two family members P2X receptors that are ligand-gated ion channels and P2Y receptors that are G protein-coupled receptors (GPCRs) [5-7]. Based on its homology with additional P2 receptors p2y5 was initially proposed to be a nucleotide-receptor but it was consequently shown to be insensitive to nucleotides [14] and to bind lysophosphatidic acid (LPA) [15]. Similarly p2y10 is a lysophospholipid receptor that is not triggered by nucleotides [16]. The P2Y14 receptor (also known as GPR105) is the most recent addition to the P2Y receptor family [17 18 P2Y14 is definitely specifically triggered by nucleotide sugars including UDP-glucose and it is insensitive to ADP/ATP and UTP [18]. While UDP-glucose is used in the rate of metabolism of nucleotide sugars it is also released by cells and functions as an autocrine activator of the P2Y14 receptor. Most nucleotides are rapidly degraded by ectonucleotidases after their launch but NNC 55-0396 UDP-glucose resists hydrolysis by these enzymes [19]. While virtually all cells launch nucleotides under basal conditions [20] this launch can be accentuated in response to stimuli leading to activation of purinergic receptors [21]. UDP-glucose extracellular ATP and adenosine are growing as immune-regulatory factors known as DAMPs (damage associated molecular pattern) molecules [22 23 DAMPs initiate sterile inflammatory reactions as opposed to PAMP (pathogen connected molecular patterns) which perpetuate infectious pro-inflammatory reactions [23-26]. The part of P2Y14 as an inflammatory mediator was suggested based on its high manifestation levels in immune cells and on the improved launch of its ligand UDP-glucose by damaged cells [17 20 27 In addition to immune cells several tissues including the mind the gastro-intestinal tract the kidney and the lung communicate P2Y14 mRNA [18]. Individuals with cystic fibrosis and asthma secrete high amounts of UDP-glucose in their lungs [27 33 and P2Y14 activation by UDP-glucose in airway epithelial cells leads to IL-8 secretion [34]. Furthermore injection of UDP-glucose into the mouse uterus induces the recruitment of neutrophils into the endometrium [35]. Another indicator of the inflammatory part of P2Y14 is the up-regulation of its mRNA manifestation by lipopolysaccharides (LPS) [35 36 However while purinergic signaling has been established in the modulation of renal swelling the part of P2Y14 in mediating immune responses in the kidney has not been described. The objective of this study was consequently to examine the potential participation of this receptor in the.