Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells.
During progression of chronic renal disease, qualitative and quantitative changes in the composition of tubular basement membranes (TBMs) and interstitial matrix occur. Transforming growth factor (TGF)-beta(1)-mediated activation of tubular epithelial cells (TECs) is speculated to be a key contributor to the progression of tubulointerstitial fibrosis. To further understand the pathogenesis associated with renal fibrosis, we developed an in vitro Boyden chamber system using renal basement membranes that partially mimics in vivo conditions of TECs during health and disease. Direct stimulation of TECs with TGF-beta(1)/epithelial growth factor results in an increased migratory capacity across bovine TBM preparations. This is associated with increased matrix metalloproteinase (MMP) production, namely MMP-2 and MMP-9. Indirect chemotactic stimulation by TGF-beta(1)/EGF or collagen type I was insufficient in inducing migration of untreated TECs across bovine TBM preparation, suggesting that basement membrane integrity and composition play an important role in protecting TECs from interstitial fibrotic stimuli. Additionally, neutralization of MMPs by COL-3 inhibitor dramatically decreases the capacity of TGF-beta(1)-stimulated TECs to migrate through bovine TBM preparation. Collectively, these results demonstrate that basement membrane structure, integrity, and composition play an important role in determining interstitial influences on TECs and subsequent impact on potential aberrant cell-matrix interactions.
Zeisberg
Michael
M
Department of Medicine and the Liver Center, Program in Matrix Biology, Renal, and Gastroenterology Divisions, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Maeshima
Yohei
Y
Mosterman
Barbara
B
Kalluri
Raghu
R
D000328:Adult; D000818:Animals; D001485:Basement Membrane / Q000473:pathology / Q000502:physiology; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D004591:Electrophoresis, Polyacrylamide Gel; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000473:pathology / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9