Arginine vasopressin stimulates mesangial cell proliferation by activating the 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 cell cycle. AVP-stimulated mesangial cell growth by activating both the Ras mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) cell signaling pathways. Both the selective PI3K inhibitor LY-294002 and the MAPK kinase (MEK) inhibitor PD-98059 inhibited AVP-stimulated mesangial cell proliferation. However, LY-294002 was more potent, indicating an important role for PI3K activation in AVP-stimulated mesangial cell proliferation. AVP appeared to exert its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the epidermal growth factor receptor (EGF-R). Pretreatment with the tyrphostin-derived EGF-R antagonist AG-1478 inhibited mesangial cell proliferation as well as the activation of extracellular signal-regulated kinase 1/2 (ERK1/2 or p42/p44(MAPK)), and p70S6 kinase, a downstream effector of PI3K, providing evidence that MAPK and PI3K activation, respectively, occurred downstream of EGF-R activation. Treatment with rapamycin, an inhibitor of the p70S6 kinase activator mTOR, also resulted in growth inhibition, further suggesting the importance of the PI3K signaling pathway in AVP-induced proliferation. AVP treatment appeared to transactivate EGF-R by inducing tyrosine phosphorylation of the Ca(2+)/protein kinase C (PKC)-dependent nonreceptor tyrosine kinase, Pyk2, leading to Pyk2/c-Src association and c-Src activation. This was followed by association of c-Src with EGF-R and EGF-R activation. These data suggested that AVP-stimulated Pyk2 tyrosine phosphorylation to activate c-Src, thereby leading to EGF-R transactivation.
Ghosh
P M
PM
Department of Surgery, University of Texas Health Science Center at San Antonio 78229, USA.
Mikhailova
M
M
Bedolla
R
R
Kreisberg
J I
JI
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D005920:Glomerular Mesangium / Q000166:cytology* / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D012076:Renal Agents / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D019061:src-Family Kinases
D001127:Arginine Vasopressin; D000081247:CSK Tyrosine-Protein Kinase; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005419:Flavonoids; D051418:Focal Adhesion Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D012076:Renal Agents; D019893:Ribosomal Protein S6 Kinases; D019061:src-Family Kinases; C496054:Ptk2b protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one