Differential expression of transforming growth factor-beta isoforms and receptors in experimental membranous nephropathy.
In membranous nephropathy (MN) overproduction of matrix by glomerular epithelial cells (GEC) is believed to be responsible for glomerular basement membrane thickening and spikes. We studied experimental MN in rats (passive Heymann nephritis, PHN) at 5, 10 and 30 days. PHN rats exhibited a marked increase in GEC immunostaining for TGF-beta 2 at all time points. TGF-beta 3 staining was increased at day 10 only, and TGF-beta 1 was unchanged. Glomerular mRNA for TGF-beta 2 and -beta 3 was increased by day 5 when urine protein increased, whereas TGF-beta 1 was not. TGF-beta 2 bioactivity was increased at day 5. There was also a marked increase in GEC immunostaining for TGF-beta receptor type I (T beta IR) and TGF-beta receptor type II (T beta IIR) at all time points in PHN. mRNA levels for both receptors increased at day 5. Increases in protein expression and mRNA levels for the TGF-beta 2 and -beta 3 isoforms, and T beta IR and T beta RII were prevented by complement depletion. We conclude that complement-mediated injury to the GEC in vivo is associated with the up-regulation of TGF-beta 2 and -beta 3 isoforms, an increase in TGF-beta 2 bioactivity, and an increase in T beta RI and T beta RII expression. This contrasts with changes in TGF-beta 1 reported in mesangial disease, suggesting that TGF-beta 2 and -beta 3 may be important in diseases of the GEC. The differential expression of TGF-beta isoforms and receptors may be important determinants of the GEC response to injury.
Shankland
S J
SJ
Division of Nephrology, University of Washington, Seattle, USA.
Pippin
J
J
Pichler
R H
RH
Gordon
K L
KL
Friedman
S
S
Gold
L I
LI
Johnson
R J
RJ
Couser
W G
WG
D000818:Animals; D015433:Glomerulonephritis, Membranous / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000737:chemistry*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000032:analysis* / Q000235:genetics
D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta