TY - JOUR
T1 - Role for transforming growth factor-β1 in Alport renal disease progression
AU - Sayers, Robinlyn
AU - Kalluri, Raghuram
AU - Rodgers, Kathyrn D.
AU - Shield, Charles F.
AU - Meehan, Daniel T.
AU - Cosgrove, Dominic
N1 - Funding Information:
This work was supported by National Institutes of Health grants 1R01 DK50280 (D.C.), 1R01 DK51711 (R.K.), and IRPG 1R01 DK55000 (D.C.) and 1R01 DK55001 (R.K.). R.L.S. was supported by a National Institutes of Health postdoctoral training fellowship via the minority supplement program through the NIDDK. We are grateful to H.L. Moses (Vanderbilt University) for his gift of the TGF-β1 cDNA. We give thanks to John (Skip) Kennedy for his help in the preparation of figures and to James Askew for his help in the maintenance and typing of animals.
PY - 1999
Y1 - 1999
N2 - Background. Alport syndrome results from mutations in either the α3(IV), α4(IV), or α5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen α3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-β1 (TGF-β1) in Alport renal disease pathogenesis. Methods. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-β1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-β1 expression using RNase protection. Results. The mRNAs encoding TGF-β1 (in both mouse and human), entactin, fibronectin, and the collagen α1(IV) and α2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. Conclusions. The concomitant accumulation of mRNAs encoding TGF-β1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-β1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.
AB - Background. Alport syndrome results from mutations in either the α3(IV), α4(IV), or α5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen α3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-β1 (TGF-β1) in Alport renal disease pathogenesis. Methods. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-β1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-β1 expression using RNase protection. Results. The mRNAs encoding TGF-β1 (in both mouse and human), entactin, fibronectin, and the collagen α1(IV) and α2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. Conclusions. The concomitant accumulation of mRNAs encoding TGF-β1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-β1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.
KW - Alport syndrome
KW - Diabetes
KW - Extracellular matrix
KW - IDDM
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=0032701879&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032701879&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.1999.00744.x
DO - 10.1046/j.1523-1755.1999.00744.x
M3 - Article
C2 - 10571774
AN - SCOPUS:0032701879
SN - 0085-2538
VL - 56
SP - 1662
EP - 1673
JO - Kidney International
JF - Kidney International
IS - 5
ER -