Angiotensin II-induced modulation of rat mesangial cell phenotype.
Inhibition of angiotensin II (AII) can ameliorate the severity of experimental radiation nephropathy. To determine the ability of AII to modulate mesangial cell phenotype, primary cultures of rat mesangial cells (passage number 6-11) were placed in serum-free medium 24 h prior to addition of AII (10(-9)-10(-5) M); control cells received serum-free medium alone. Cells were maintained in serum-free medium for a further 48 h. Addition of AII to quiescent mesangial cells resulted in significant (P < 0.05) time- and/or dose-dependent increases in Fn and Pail mRNA and/or immunoreactive protein. No significant change was observed in terms of Tgfb1 mRNA. A significant increase in total Tgfb1 protein (P < 0.01) secreted by AII-treated mesangial cells was noted; however, this increase was primarily in terms of latent TGF-beta; the relative proportion of active TGF-beta secreted decreased after AII incubation. AII had no effect on the activity of Mmp2 or Mmp9. However, AII-treated mesangial cells did show an increase in the amount of tissue inhibitor of metalloproteinase-2 (Timp2) immunoreactive protein secreted into the medium. The AII-mediated increase in Pail mRNA levels appeared due in part to activation of the AT1 receptor and was independent of TGF-beta; co-incubation with TGF-beta-neutralizing antibody failed to inhibit the AII-mediated increase in Pail mRNA. Thus mesangial cells treated with AII exhibit a pro-fibrosis phenotype.
Zhang
X
X
Department of Radiology, The University of Iowa, Iowa City 52242, USA.
O'Malley
Y
Y
Robbins
M E
ME
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9