Dipyridamole inhibits TGF-beta-induced collagen gene expression in human peritoneal mesothelial cells

Background. Peritoneal matrix accumulation is characteristic of peritoneal fibrosis (PF). Continuous ambulatory peritoneal dialysis (CAPD) patients wh o had persistent transforming growth factor-beta (TGF-beta) in their draine d effluent had an increased risk of PF. We previously reported that TGF-bet a stimulates the expression of types I and III collagen mRNA in cultured hu man peritoneal mesangial cells (HPMCs), which may predispose them to develo p PF. Pharmacological interventions to attenuate TGF-beta -stimulated matri x accumulation in HPMC may have therapeutic potential for the treatment of PF. The SMAD family and the extracellular signal-regulated protein kinase ( ERK1/2, p44/p42) pathways have been shown to participate in TGF-beta signal ing. Our current study identified these signal pathways in HPMCs and invest igated the molecular mechanisms involved in the inhibitory effects of dipyr idamole on TGF-beta -induced collagen gene expression in HPMCs. Methods. HPMCs were Cultured from human omentum by an enzyme digestion meth od. Expression of collagen alpha1(I) mRNA was determined by Northern blotti ng. The SMAD proteins and the ERK1/2 activity were determined by Western bl otting. Results. TGF-beta -stimulated collagen alpha1(I) mRNA expression of HPMC wa s inhibited by dipyridamole in a dose-dependent manner. Smad2 and ERK1/2 we re activated in response to TGF-beta, however. TGF-beta had little effect o n the protein expression of Smad4. The addition of PD98059, which blocked a ctivation of ERK1/2, suppressed TGF-beta -induced collagen alpha1(I) mRNA e xpression in a dose-dependent manner. At a concentration that inhibited col lagen gene expression (17 mug/ mL), dipyridamole suppressed ERK1/2 activati on by TGF-beta. In contrast. the same concentration of dipyridamole had no effect on TGF-beta -induced activation of Smad2. Conclusion. Dipyridamole inhibits TGF-beta -induccd collagen gene expressio n in HPMC through modulation of the ERK pathway. Our study of dipyridamole may provide therapeutic basis for clinical applications in the prevention o f PF.