MYOFIBROBLASTS IN EXPERIMENTAL HYDRONEPHROSIS

Interstitial fibrosis is a common outcome of long-term ureteral obstru ction. One pathological arm of the fibrotic reaction in diverse tissue loci and experimental models is the retraction of granulation tissue. The role of the myofibroblast in granulation tissue contraction and f ibrocontractive diseases has been well established, but the mechanisms leading to differentiation of fibroblasts during the evolution of inf lammation are not yet fully clarified. Investigators using other model systems have shown that the macrophage-derived transforming growth fa ctor-beta 1 (TGF-beta 1) may be pivotal in the process of myofibroblas t modulation. Our laboratory has shown that the unilateral ureteral ob struction in the rat is characterized by a 20-fold increment in filtra tion renal cortical interstitial macrophages, an increase in cortical TGF-beta 1 gene expression, which parallels the infiltrating macrophag e burden, and immunolocalization of this peptide growth factor in clos e proximity to resident interstitial fibroblasts. Because fo this mode l's features, it was our aim to assess whether a myofibroblastic modul ation was operant in the renal cortex of obstructed rat kidneys versus the control contralateral unobstructed kidney specimens. Immunolabeli ng for alpha-smooth muscle actin protein, the mRNA expression for this cytoskeletal component exhibited 3.7-, 15.7-, and 4.1-fold increments in the renal cortex of obstructed kidneys versus the contralateral un obstructed kidney specimens at 24, 48, and 96 hours after unilateral u reteral obstruction, respectively. Whole body X-irradiation, administe red to rats 11 days before proximal left ureteral ligation, significan tly lowered cortical interstitial macrophage number, cortical TGF-beta and alpha-smooth muscle actin mRNA levels as well as the intensity of immunolabeling for alpha-smooth muscle actin from 12 to 96 hours afte r unilateral ureteral obstruction. These data support a postulate that renal cortical TGF-beta 1, derived from the infiltration macrophage, in part, contributes to the subsequent interstitial fibrosis response to renal injury by fostering the modulation of fibroblasts to myofibro blasts within the renal cortex after ureteral obstruction.