Abnormal growth and clonal proliferation of fibroblasts in an animal model of unilateral ureteral obstruction.

The time course for the development of renal interstitial fibrosis (RIF) in rats between days 5 and 25 after unilateral ureteral obstruction (UUO) was studied. In kidneys with UUO under histological examination, an interstitial fibrosis was observed after more than 10 days with progression up to day 25. On day 5, collagen peptidase activity in homogenates of UUO kidneys was about 50% higher than in controls but gradually declined afterwards until reaching the level obtained from contralateral kidneys (CL) on day 25. 10 days after UUO, renal hydroxyproline content was elevated about twofold as compared to CL and sham-operated rats, and increased considerably by day 25 of UUO. In primary cultures of cells obtained from UUO kidneys, fibroblast proliferation increased regardless of the extent of fibrosis. This could be a result of an early inflammatory process. Renal fibroblasts from rats are heterogenous when studied in vitro. When fibroblasts of passage 1 obtained from kidneys 25 days after UUO were plated at low density, the number of mitotic type I clones was elevated 5.5-fold as compared with cultures from CL kidneys. The majority of type I clones in UUO cultures from fibrotic kidneys developed in an unusual fashion with formation of three-dimensional structures. The changes detectable under the unfavorable conditions of clonal culture suggest phenotypical differentiation of a small fraction of fibroblasts from kidneys with RIF. These cells are able to overgrow cell monolayers forming circular growing colonies. Obviously, one needs to distinguish between intensive proliferation as a consequence of acute inflammation, and the changes in phenotype of a small fraction of renal fibroblasts which are resistant to normal physiologic regulative mechanisms in cell culture. The latter may contribute to matrix disorders and RIF.