Role for transforming growth factor-beta 1 in Alport renal disease progression

Background. Alport syndrome results from mutations in either the alpha 3(IV ), alpha 4(IV), or alpha 5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequen cy sensorineural hearing loss. A mouse model for an autosomal form of Alpor t syndrome [collagen alpha 3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta 1 (TGF-beta 1) in Alport renal disease path ogenesis. Method's. Kidneys from normal and Alport mice, taken at different stages du ring the course of renal disease progression, were analyzed by Northern blo t, in situ hybridization, and immunohistology for expression of TGF-beta 1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta 1 expression using RNase protection. Results. The mRNAs encoding TGF-beta 1 (in both mouse and human), entactin, fibronectin, and the collagen alpha 1(IV) and alpha 2(IV) chains were sign ificantly induced in total kidney as a function of Alport renal disease pro gression. The induction of these specific mRNAs was observed in the glomeru lar podocytes of animals with advanced disease. Type IV collagen, laminin-1 , and fibronectin were markedly elevated in the tubulointerstitium at 10 we eks, but not at 6 weeks, suggesting that elevated expression of specific mR NAs on Northern blots reflects events associated with tubulointerstitial fi brosis. Conclusions. The concomitant accumulation of mRNAs encoding TGF-beta 1 and extracellular matrix components in the podocytes of diseased kidneys may re flect key events in Alport renal disease progression. These data suggest a role for TGF-beta 1 in both glomerular and tubulointerstitial damage associ ated with Alport syndrome.