Role for transforming growth factor-β1 in Alport renal disease progression

Robinlyn Sayers, Raghuram Kalluri, Kathyrn D. Rodgers, Charles F. Shield, Daniel T. Meehan, Dominic Cosgrove

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1662-1673
Number of pages12
JournalKidney International
Volume56
Issue number5
DOIs
StatePublished - 1999

Keywords

  • Alport syndrome
  • Diabetes
  • Extracellular matrix
  • IDDM
  • TGF-β

ASJC Scopus subject areas

  • Nephrology

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