Unilateral ureteral obstruction (UUO) leads to interstitial fibrosis of the obstructed kidney, and transforming growth factor-beta1 (TGF-beta1) is thought to play an important role in this process. Although increased TGF-beta1 mRNA expression in the obstructed kidney has been demonstrated, the source of the increased TGF-beta1 remains to be elucidated. To determine the precise localization of TGF-beta1 in the obstructed kidney, we examined TGF-beta1 mRNA expression using in situ hybridization and competitive RT-PCR in rats with UUO. In situ hybridization demonstrated that TGF-beta1 mRNA expression was preferentially increased in tubular epithelial cells and to a lesser degree in infiltrating macrophages in obstructed kidneys. Quantitative analysis using competitive RT-PCR in microdissected nephron segments revealed that levels of TGF-beta1 mRNA in obstructed kidneys relative to control kidneys increased significantly in proximal tubules, thick ascending limbs of Henle, and distal convoluted tubules, whereas those in glomeruli and collecting ducts did not change significantly. Of the tubular segments, the proximal tubules appeared to predominantly contribute to increased TGF-beta1 mRNA. Our findings suggest that renal tubules, particularly proximal tubules, are the main contributors to increased TGF-beta1 mRNA expression in obstructed kidneys and to the subsequent interstitial fibrosis.

Recent studies have revealed that endothelin-1 (ET-1) is a potent mitogen for mesangial cells in vitro. To determine whether ET-1 exerts the mitogenic action on mesangial cells in vivo, we examined the glomerular expression of ET-1 and its receptors in a rat model of mesangial proliferative glomerulonephritis and assessed the effect of a specific endothelin A (ET(A)) receptor antagonist, FR139317, on mesangial cell proliferation in this model. The levels of preproET-1 mRNA expression and ET-1 protein production in glomeruli increased markedly on days 4 and 7 after disease induction, and the levels changed in concordance with the glomerular cell proliferation. In contrast, the level of ET(A) receptor mRNA initially decreased on day 1, and thereafter increased on days 4 and 7. Administration of FR139317 to rats with experimental glomerulonephritis induced a significant reduction in mesangial cell proliferation. In addition, in situ hybridization of preproET-1 mRNA and double-immunolabeling of ED-1 and OX-7 in a mirror image section revealed that the principal cell expressing ET-1 in glomeruli were infiltrating macrophages on day 1, and they were replaced by mesangial cells on day 4. These findings indicate that ET-1 functions as a potent mitogen for mesangial cells in vivo in an autocrine or paracrine fashion.

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This paper reviews the expression and localization of proteins of the TGF-β system in the kidney, i.e. TGF-β isoforms, latent TGF-β binding protein, and receptors. There is heterogeneity of TGF-β isoforms, binding proteins and receptors. TGF-βs are more evenly distributed among different segments of the nephron than TGF-β receptors, and are expressed by almost all cell types in the kidney. The spatial distribution of TGF-β and its signaling receptor may help to better understand the biologic function of TGF-β in the kidney.