Arginine vasopressin stimulates mesangial cell proliferation by activatingthe epidermal growth factor receptor

The potent vasoconstrictor arginine vasopressin (AVP) is also a mitogen for mesangial cells. Treatment with AVP decreased transit time through the cel l cycle. AVP-stimulated mesangial cell growth by activating both the Ras mi togen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) cell signaling pathways. Both the selective PI3K inhibitor LY-29400 2 and the MAPK kinase (MEK) inhibitor PD-98059 inhibited AVP-stimulated mes angial cell proliferation. However, LY-294002 was more potent, indicating a n important role for PI3K activation in AVP-stimulated mesangial cell proli feration. AVP appeared to exert its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the epidermal growth factor re ceptor (EGF-R). Pretreatment with the tyrphostin-derived EGF-R antagonist A G-1478 inhibited mesangial cell proliferation as well as the activation of extracellular signal-regulated kinase 1/2 (ERK1/2 or p42/ p44(MAPK)), and p 70S6 kinase, a downstream effector of PI3K, providing evidence that MAPK an d PI3K activation, respectively, occurred downstream of EGF-R activation. T reatment with rapamycin, an inhibitor of the p70S6 kinase activator mTOR, a lso resulted in growth inhibition, further suggesting the importance of the PI3K signaling pathway in AVP-induced proliferation. AVP treatment appeare d to transactivate EGF-R by inducing tyrosine phosphorylation of the Ca2+/p rotein kinase C (PKC)-dependent nonreceptor tyrosine kinase, Pyk2, leading to Pyk2/c-Src association and c-Src activation. This was followed by associ ation of c-Src with EGF-R and EGF-R activation. These data suggested that A VP-stimulated Pyk2 tyrosine phosphorylation to activate c-Src, thereby lead ing to EGF-R transactivation.