Divergent expression of EtA and EtB receptors in response to cyclosporine in mesangial cells.
We examined the effects of cyclosporine (Cy) on preproendothelin-1 (prepro Et-1) and both Et receptors, A-type (EtA) and B-type (EtB), in rat glomerular mesangial cells. Cy at 10(-5) mol/L, the concentration relevant to tissue levels in vivo, increased mRNA for prepro Et-1 after both 1 and 3 hours to 183 +/- 14% (n = 8) and 147 +/- 12% (n = 9) of levels seen in control cells. A similar pattern was observed at a lower dose of Cy (10(-6) mol/L, the concentration relevant to plasma levels in vivo): at 1 hour, expression increased to 146 +/- 15% (n = 5); at 3 hours, expression was 159 +/- 25% (n = 8). Concomitant with these changes in expression of prepro Et-1 mRNA, the Et-1 protein nearly doubled at 3 hours. Both EtA and EtB mRNA were expressed in unstimulated mesangial cells and were affected differently by Cy. Little change was observed in the EtA mRNA. In contrast, EtB mRNA increased with Cy (10(-5) mol/L) up to 129 +/- 8% (n = 6) at 1 hour and 265 +/- 62% (n = 3) at 3 hours. A similar effect was seen with the lower dose of Cy: EtB expression increased to 129 +/- 9% (n = 6) of control value at 1 hour and 253 +/- 74% (n = 4) at 3 hours. These results indicate that Cy enhances expression of mRNA for prepro Et-1 and production of mature Et-1 by glomerular mesangial cells. Further, Cy has differential effects on EtA and EtB, affecting EtA minimally while markedly increasing the expression of EtB. These results constitute the first demonstration that Et receptor subtypes are modulated in a pathophysiological setting. The divergent modulation of EtA and EtB raises the possibility that there are differences in contribution of each of the receptor subtypes to pathophysiological mechanisms of Cy toxicity.
Takeda
M
M
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Iwasaki
S
S
Hellings
S E
SE
Yoshida
H
H
Homma
T
T
Kon
V
V
D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D016232:Endothelins / Q000032:analysis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000737:chemistry* / Q000166:cytology* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D016572:Cyclosporine