Role for transforming growth factor-beta1 in alport renal disease progression.
BACKGROUND
Alport syndrome results from mutations in either the alpha3(IV), alpha4(IV), or alpha5(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 alpha3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta1 (TGF-beta1) 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-beta1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta1 expression using RNase protection.


RESULTS
The mRNAs encoding TGF-beta1 (in both mouse and human), entactin, fibronectin, and the collagen alpha1(IV) and alpha2(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-beta1 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-beta1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.
Sayers
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Boystown National Research Hospital, 555 North 30th Street, Omaha, Nebrasa, 68131, USA.
Kalluri
R
R
Rodgers
K D
KD
Shield
C F
CF
Meehan
D T
DT
Cosgrove
D
D
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005921:Glomerulonephritis / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009394:Nephritis, Hereditary / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta