Differential effects of angiotensin II and transforming growth factor beta on the production of heparan sulfate proteoglycan by mesangial cells in vitro.
This study approaches the question of whether angiotensin II (AngII) and transforming growth factor beta (TGF-beta) are important mediators for mesangial heparan sulfate proteoglycan (HSPG) production. This might explain the beneficial effects of angiotensin-converting enzyme inhibitors observed in several kidney diseases independent from their hemodynamic effects. Metabolic-labeling studies revealed that AngII induced a decrease of HSPG synthesis with decreases in N-sulfation of the glycosaminoglycan side chains. ELISA measurements with a heparan sulfate (HS)-specific monoclonal antibody confirmed that AngII decreased HS production. AngII increased TGF-beta production in a dose-dependent fashion. Specific mRNA for the large basement membrane HSPG (perlecan) decreased, whereas mRNA for TGF-beta increased after incubation with AngII. Blockade of the Subtype 1 Ang-II receptor (ATR1) reversed both the effects of AngII on HSPG and TGF-beta production. Coincubation of the mesangial cells with neutralizing antibodies against TGF-beta significantly reduced the production of HS as compared with control and AngII. These results indicate that the decrease in HS synthesis induced by AngII is not mediated by an increase in TGF-beta, but on the contrary, the increase in TGF-beta partially counteracts the inhibition of HS production by AngII. Considering the important role of HSPG in maintaining the glomerular charge barrier, cell proliferation, and matrix interaction, downregulation of the production of this molecule by increased local AngII concentrations could have important consequences, such as albuminuria and matrix expansion.
van Det
N F
NF
Department of Nephrology, Leiden University Hospital, The Netherlands.
Tamsma
J T
JT
van den Born
J
J
Verhagen
N A
NA
van den Heuvel
L P
LP
Löwik
C W
CW
Berden
J H
JH
Bruijn
J A
JA
Daha
M R
MR
van der Woude
F J
FJ
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D009844:Oligosaccharides / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D009844:Oligosaccharides; D011509:Proteoglycans; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; C071927:perlecan