Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis.
Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.
Morath
Christian
C
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Dechow
Claudius
C
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Lehrke
Ingo
I
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Haxsen
Volker
V
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Waldherr
Rüdiger
R
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Floege
Jürgen
J
Department of Nephrology, University of Aachen, Aachen, Germany.
Ritz
Eberhard
E
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Wagner
Jürgen
J
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism*; D015474:Isotretinoin / Q000494:pharmacology; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013599:Systole; D018800:Thy-1 Antigens / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D012176:Retinoids; C508962:Tgfb1 protein, rat; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015474:Isotretinoin