Cyclic stretch activates p38 SAPK2-, ErbB2-, and AT1-dependent signaling in bladder smooth muscle cells

Cyclic mechanical stretch of bladder smooth muscle cells (SMC) increases ra tes of DNA synthesis and stimulates transcription of the gene for heparin-b inding epidermal growth factor-like growth factor (HB-EGF), an ErbB1/EGF re ceptor ligand that has been linked to hypertrophic bladder growth. In this study we sought to clarify the signaling pathways responsible for mechanotr ansduction of the stretch stimulus. HB-EGF mRNA levels, DNA synthesis, and AP-1/Ets DNA binding activities were induced by repetitive stretch of prima ry culture rat bladder SMC. Inhibitors of the p38 SAPK2 pathway, the angiot ensin receptor type 1 (AT1), and the ErbB2 tyrosine kinase reduced each of these activities, while an inhibitor of the extracellular signal-regulated kinase mitogen-activated protein kinase (Erk-MAPK) pathway had no effect. S tretch rapidly activated stress-activated protein kinase 2 (p38 SAPK2) and Jun NH2-terminal kinase (JNK)/SAPK pathways but not the Erk-MAPK pathway an d induced ErbB2 but not ErbB1 phosphorylation. Angiotensin II (ANG II) a bl adder SMC mitogen previously linked to the stretch response, did not activa te ErbB2, and ErbB2 activation occurred in response to stretch in the prese nce of an ANG receptor inhibitor, indicating that activation of the AT1-med iated pathway and the ErbB2-dependent pathway occurs by independent mechani sms. p38 SAPK2 and JNK/SAPK signaling also appeared to be independent of th e ErbB2 and AT1 pathways. These findings indicate that stretch-stimulated D NA synthesis and gene expression in normal bladder SMC occur via multiple i ndependent receptor systems (e.g., AT1 and ErbB2) and at least one MAPK pat hway (p38 SAPK2). Further, we show that the Erk-MAPK pathway, which in most systems is linked to receptor-dependent cell growth responses, is not invo lved in progression to DNA synthesis or in the response of the HB-EGF gene to mechanical forces.