P2 purinergic receptor dysregulation in urologic disease

Abstract

P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia. P2 purinergic receptors are likewise indirectly associated with these disorders via receptor-mediated inflammation and pain, a common characteristic across most urologic disorders. Furthermore, select P2 purinergic receptors are overexpressed in urologic cancer including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma, and pre-clinical studies depict P2 purinergic receptors as potential therapeutic targets. Herein, we highlight the compelling evidence for the exploration of P2 purinergic receptors as biomarkers and therapeutic targets in urologic cancers and other urologic disease. Likewise, there is currently optimism for P2 purinergic receptor-targeted therapeutics for the treatment of inflammation and pain associated with urologic diseases. Further exploration of the common pathways linking P2 purinergic receptor dysregulation to urologic disease might ultimately help in gaining new mechanistic insight into disease processes and therapeutic targeting.

Keywords: Extracellular ATP; P2X; P2Y; Prostate cancer; Purinergic receptors; Urologic disease.

Fig. 1

P2 purinergic receptor signaling. Extracellular ATP (eATP) is released from injured, necrotic, and apoptotic cells via exocytosis or pannexin channels. Increased concentrations of eATP recruit (e.g., neutrophils) and activate (e.g., macrophages) immune cells. Activation of P2 purinergic receptors increases intracellular calcium initiating signaling cascades that facilitate nociceptive and neuropathic pain, inflammasome assembly and activation, and the induction of proinflammatory cytokines and chemokines

Fig. 2

P2 purinergic receptors in normal kidney function and disease. Activation of P2Y2, P2Y4, and P2X4 contributes to blood pressure maintenance. Ischemia and reperfusion result in increased extracellular nucleotides. Activation of P2X4, P2X7, and P2Y14 initiates signaling cascades that promote chemokine induction, renal tubule necrosis and apoptosis, and neutrophil infiltration contributing to acute kidney injury. P2X7 activation contributes to chronic kidney disease pathogenesis via the NLRP3 inflammasome, while P2Y2 is protective against the same disease. P2X7 activation might also affect cystogenesis via the ERK1/2 pathway culminating in polycystic disease, a risk factor for kidney cancer. P2X6 activation increases kidney cancer cell invasiveness via ERK1/2 and MMP9 signaling

Fig. 3

P2 purinergic receptor mRNA expression in TCGA public datasets. P2 purinergic receptor expression is dysregulated in urologic cancers. The heatmap shows significantly increased (yellow) and decreased (blue) P2 purinergic receptor mRNA expression in cancer compared to normal (P < 0.01) as assessed by the Wanderer tool. P2 purinergic receptors were assessed in the urothelial carcinoma (n: normal (N) = 19; tumor (T) = 267), kidney chromophobe (n: normal (N) = 25; tumor (T) = 66), kidney clear cell (n: Normal (N) = 72; tumor (T) = 518), kidney papillary cell (n: normal (N) = 30; tumor (T) = 198), and prostate adenocarcinoma (n: normal (N) = 52; tumor (T) = 374) datasets

Fig. 4

P2 purinergic receptors in bladder normal function and disease. Urothelial stretch releases ATP which activates P2X receptors to maintain micturition reflex for normal bladder emptying. Activation of P2Y6 results in ATP release, which activates P2X3, increasing voiding frequency and promoting urinary incontinence. Hydrolysis of ATP results in ADP which activates P2Y1 receptors, which decreases voiding frequency. P2Y12 inhibition of adenylyl cyclase results in bladder smooth muscle contraction which increases voiding frequency in overactive bladder syndrome

Fig. 5

P2 purinergic receptors in prostate normal function and disease. P2X1 receptors are involved in prostate contractility. Activation of P2X3 facilitates pain transmission, while P2X7 activation induces proinflammatory cytokines, both contributing to prostatitis. Activation of P2Y2 promotes prostate cancer cell migration and invasion via the p38, Akt, ERK1/2, MMP3, or MMP13 signaling