Chronic unilateral ureteral obstruction is associated with interstitial fibrosis and tubular expression of transforming growth factor-beta.

Chronic unilateral ureteral obstruction (UUO) results in interstitial fibrosis and nephron damage associated with irreversible loss of function. Collagen is increased in UUO, but detailed studies of rat renal extracellular matrix changes in UUO have not been carried out. Acute (3-day) obstruction results in increases in renal macrophages and the fibrogenic cytokine transforming growth factor-beta (TGF-beta), but their involvement in longer-term obstruction and fibrosis has not been studied. In the present experiments, kidneys of rats after UUO of 1, 2, 3, 7, 14, 21, and 28 days' duration were used. Trichrome staining, measurement of interstitial volume, and immunohistochemical studies localizing collagens I, III, and IV; laminin; fibronectin; TGF-beta; and macrophages were carried out. We found increases in the interstitial space in both cortex and medulla that (a) were significant by day 7 after UUO and (b) were accompanied by increased deposition of collagen I and collagen III. Collagen IV, laminin, and fibronectin, normally associated with the basement membrane, were found both in a thickened basement membrane and in the interstitial space. Macrophages, not found in sham-operated kidneys, were found in the interstitial space after UUO. TGF-beta was found in sham cortical tubules, but not in medullary tubules. UUO was associated with little change in cortical TGF-beta, whereas at 14 days, TGF-beta was found in dilated medullary tubules. Immunohistochemical findings were confirmed with measurements of tissue TGF-beta. In summary, UUO is associated with interstitial fibrosis. The increase in extracellular matrix is due both to increases in the interstitial collagens I and III and the basement membrane-associated collagen IV, laminin, and fibronectin. Macrophages are increased after UUO, but do not seem to be associated with the fibrogenic cytokine TGF-beta. Medullary tubular synthesis of TGF-beta may be a contributing factor in the fibrosis associated with UUO.