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Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs

Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea

Submitted 6 December 2005 ; accepted in final form 6 January 2006

Although ATP has been shown to act as a modulator in various kidney functions, its effect on renal proximal tubule cell (PTC) proliferation has not been elucidated. This study investigated the effect of ATP on cell proliferation and the effect of its related signal pathways on primary cultured PTCs. Treatment with >10^–5 M ATP for 1 h stimulated incorporation of thymidine and bromodeoxyuridine. ATP (10^–4 M)-induced stimulation of thymidine incorporation was blocked by suramin (a P2X and P2Y receptor antagonist), reactive blue 2 (a P2Y receptor antagonist), MRS-2159 (a P2X₁ receptor antagonist), and MRS-2179 (a P2Y₁ receptor antagonist). ATP increased intracellular Ca²⁺ concentration, which was blocked by suramin, methoxyverapamil, and EGTA. ATP-induced stimulation of cell proliferation was also blocked by EGTA (an extracellular Ca²⁺ chelator), methoxyverapamil (a Ca²⁺ antagonist), and nifedipine (an L-type Ca²⁺ channel blocker), suggesting a role for Ca²⁺ influx. ATP-induced phosphorylation of p38 and p44/42 MAPKs was blocked by nifedipine. ATP increased expression levels of cyclin-dependent kinase (CDK)-2, CDK-4, and cyclin E, which were blocked by suramin, reactive blue 2, MRS-2179, MRS-2159, and nifedipine. However, ATP decreased expression levels of p21^WAF1/Cip1 and p27^kip1. ATP-induced stimulation of thymidine incorporation and increase of CDK-2 and CDK-4 expression were blocked by SB-203580 (a p38 MAPK inhibitor) and PD-98059 (an MEK inhibitor), but not by SP-600125 (a JNK inhibitor). In conclusion, ATP stimulates proliferation by increasing intracellular Ca²⁺ concentration and activating p38, p44/42 MAPKs, and CDKs in PTCs.

cell proliferation; calcium influx

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