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P2Y-receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway.

ABSTRACT: 1. Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of exogenous ATP on human mesangial cells in culture were studied. 2. Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on [(3)H]thymidine incorporation, the activation of mitogen-activated protein kinase and the cell number were studied. The involved P2-receptors were characterized pharmacologically. In addition, we searched for mRNA for P2Y- and P2X-receptors by RT-PCR. 3. ATP (0.1-300 micro M) and related nucleotides induced a significant increase in [(3)H]thymidine incorporation up to 220% of control. The adenine nucleotides ATP and ADP were about equally effective. Also ATP-gamma-S, UTP, ADP-beta-S and 2-m-thio-ADP induced a weaker response. UDP and alpha-beta-methylene-ATP failed to induce an effect on [(3)H]thymidine uptake. 4. ATP (100 micro M) induced a fast activation of the MAPK(42/44) pathway. The effects of ATP on MAPK(42/44) activation and [(3)H]thymidine incorporation were reduced by the MAPK inhibitor PD 98059. Platelet-derived growth factor (PDGF 5 ng ml(-1)) increased the cell number to more than 122% of control. ATP (10 micro M) on top of PDGF amplified PDGF induced cell proliferation to 136% of control. 5. RT-PCR products for P2Y(1,2,4,6,11,12)- and P2X(1,2,4,5,6,7)-receptor subtypes were detected in human mesangial cells. 6. ATP has mitogenic effects on human mesangial cells. DNA synthesis is increased by the activation of the MAPK(42/44) pathway. ATP amplifies PDGF-induced cell hyperplasia.

SUBMITTER: Vonend O

PROVIDER: S-EPMC1573950 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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P2Y-receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway.

Vonend Oliver O Grote Tobias T Oberhauser Vitus V Von Kügelgen Ivar I Rump Lars Christian LC

British journal of pharmacology 20030701 6

1. Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of exogenous ATP on human mesangial cells in culture were studied. 2. Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on [(3)H]thymidine incorporation, the activation of mitogen-activated protein kinase and the cell number were studied. The involved P2 ...[more]

PMID: 12871830

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Project description:Gastric cancer (GC) is the one of the most prevalent cancers and one of the leading causes of cancer-induced deaths. Previously, we found that the expression of purinergic P2Y2 receptor (P2Y2R) is increased in GC samples as compared to adjacent healthy mucosa taken from GC-diagnosed patients. In this work, we studied in detail purinergic signaling in the gastric adenocarcinoma-derived cell lines: AGS, MKN-45, and MKN-74, and compared them to a nontumoral epithelial cell line: GES-1. In GC-derived cells, we detected the expression of several purinergic receptors, and found important differences as compared to GES-1 cells. Functional studies revealed a strong contribution of P2Y2Rs in intracellular calcium increases, elicited by adenosine-triphosphate (ATP), uridine-triphosphate (UTP), and the P2Y2R agonist MRS2768. Responses were preserved in the absence of extracellular calcium and inhibited by P2Y2R antagonists. In GES-1 cells, ATP and UTP induced similar responses and the combination of P2X and P2Y receptor antagonists was able to block them. Proliferation studies showed that ATP regulates AGS and MKN-74 cells in a biphasic manner, increasing cell proliferation at 10-100 μM, but inhibiting at 300 μM ATP. On the other hand, 1-300 μM UTP, a P2Y2R agonist, increased concentration-dependent cell proliferation. The effects of UTP and ATP were prevented by both wide-range and specific purinergic antagonists. In contrast, in GES-1 cells ATP only decreased cell proliferation in a concentration-dependent manner, and UTP had no effect. Notably, the isolated application of purinergic antagonists was sufficient to change the basal proliferation of AGS cells, indicating that nucleotides released by the cells can act as paracrine/autocrine signals. Finally, in tumor-derived biopsies, we found an increase of P2Y2R and a decrease in P2X4R expression; however, we found high variability between seven different biopsies and their respective adjacent healthy gastric mucosa. Even so, we found a correlation between the expression levels of P2Y2R and P2X4R and survival rates of GC patients. Taken together, these results demonstrate the involvement of different purinergic receptors and signaling in GC, and the pattern of expression changes in tumoral cells, and this change likely directs ATP and nucleotide signaling from antiproliferative effects in healthy tissues to proliferative effects in cancer.

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P2Y-receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway.

Publications

P2Y-receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway.

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