Effect of YM218, a nonpeptide vasopressin V(1A) receptor-selective antagonist, on rat mesangial cell hyperplasia and hypertrophy.
Mesangial cell growth constitutes a key feature of progressive glomerular injury. Vasopressin (AVP), a potent peptide vasoconstrictor, acts on mesangial cells through the V(1A) receptors, inducing contraction and cell proliferation. This study examined the effects of YM218, a nonpeptide AVP V(1A) receptor-selective antagonist, on the mitogenic and hypertrophic effects of AVP in rat mesangial cells. When added to mesangial cells whose growth was arrested, AVP concentration-dependently induced hyperplasia and hypertrophy. YM218 potently prevented AVP-induced hyperplasia and hypertrophy of these cells. Furthermore, AVP stimulated endothelin (ET)-1 secretion from mesangial cells in a concentration-dependent manner and this effect was potently inhibited by YM218. ET-1 also induced hyperplasia and hypertrophy in mesangial cells and this effect was completely abolished by ET(A) receptor-selective antagonist YM598. In addition, AVP-induced hyperplasia and hypertrophy were partly inhibited by YM598. These results suggest that AVP may modulate mesangial cell growth not only by its direct action but also through the stimulation of ET-1 secretion. YM218 displays high potency in inhibiting the AVP-induced physiologic responses of mesangial cells via the V(1A) receptors and is a potent pharmacologic probe for investigating the physiologic and pathophysiologic roles of AVP in several renal diseases.
Tahara
Atsuo
A
Institute for Drug Discovery Research, Astellas Pharma Inc., 5-2-3, Toukoudai, Tsukuba, Ibaraki 300-2698, Japan. atsuo.tahara@jp.astellas.com
Tsukada
Junko
J
Tomura
Yuichi
Y
Suzuki
Takeshi
T
Yatsu
Takeyuki
T
Shibasaki
Masayuki
M
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism* / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006965:Hyperplasia; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
C501286:4'-(4,4-difluoro-5-(2-oxo-2-(4-piperidinopiperidino)ethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-methyl-3-furanilide; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D010880:Piperidines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017483:Receptors, Vasopressin; D013449:Sulfonamides; D001127:Arginine Vasopressin