title: Downregulation of vasopressin V1A receptors and activation of mitogen-activated protein kinase in rat mesangial cells cultured under high-glucose conditions.
abstract: In the present study we examined the effects of high extracellular glucose concentrations on vasopressin (AVP) V(1A)  receptor kinetics and signal transduction in cultured rat mesangial cells. Scatchard analysis of [(3) H]-AVP binding to mesangial cell plasma membranes showed that although high glucose (30 mmol/L) decreased V(1A)  receptor numbers relative to cells cultured in normal glucose (10 mmol/L), receptor affinity was not affected. This V(1A)  receptor downregulation was associated with an attenuated increase in AVP-stimulated cytosolic free calcium concentrations ([Ca(2+) ](i) ). In addition, high glucose increased both the basal and AVP-stimulated activity of the classic mitogen-activated protein kinase, namely extracellular signal-regulated kinase (ERK). Furthermore, high glucose induced activation of protein kinase C (PKC) in mesangial cells that could be inhibited by coincubation with the PKC inhibitor staurosporine (10 nmol/L). Staurosporine also markedly attenuated the high glucose-induced downregulation of V(1A)  receptors on mesangial cells and blocked the depressed [Ca(2+) ](i)  response and increased ERK activity induced by AVP. The results indicate that high extracellular glucose downregulates V(1A)  receptors on rat mesangial cells and modulates their signal transduction properties via PKC activation.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan. atsuo.tahara@jp.astellas.com
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Junko
authors.initials: J
authors.lastname: Tsukada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Yatsu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000096:biosynthesis
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose