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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Transforming Growth Factor in Rat Bladder Smooth Muscle Cell Proliferation

Departments of Pharmacology and Pharmacotherapy (M.M.B., A.C.M.M., M.S., MC.M.), Urology (M.M.B.), and Anatomy and Embryology (M.v.d.H.), Academic Medical Center, Amsterdam, The Netherlands; Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands (H.v.d.P.); and Department of Molecular Pharmacology, Rijksuniversiteit Groningen, Groningen, The Netherlands (M.S.)

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor (TGF) in both rats and patients. Because TGF can have both growth-promoting and -inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGF1, TGF2, or TGF3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC₅₀ of approximately 0.1 ng/ml) and efficacy. Such inhibition was antagonized by a specific TGF receptor antagonist and independent of the presence of serum. Mitogen-activated protein kinases (MAPKs) are involved in the control of cell growth, and all three TGF isoforms inhibited activation of the extracellular signal-regulated kinase, c-Jun NH₂-terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGF isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGF did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGF is a mediator of rat bladder hypertrophy.

Address correspondence to: Dr. Martin C. Michel, Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: m.c.michel{at}amc.nl