Renal fibrosis in mice treated with human recombinant transforming growth factor-β2

Abstract

Background. The biologic responses to transforming growth factor-β (TGF-β) suggest many potential therapeutic applications; however, in the only clinical trial to examine the effect of the systemic administration of a TGF-β isoform, patients experienced significant but reversible declines in renal function. We studied the effects of administering human recombinant TGF-β2 to adult mice. Methods. The effect of daily administration of TGF-β2 on tissue vasoconstriction, tissue levels of endothelin and angiotensin II, tissue hypoxia, and renal fibrosis were examined. Results. Daily administration of TGF-β2 at 10 or 100 μg/kg caused apparent tissue vasoconstriction that was visualized by vascular casting, with the largest impact seen in the kidney. Tissue levels of endothelin 1 and angiotensin II were significantly elevated in kidneys of treated mice, as was urinary thromboxane β2. Renal fibrosis was observed in the cortical tubular interstitium and vasculature, particularly at the cortical-medullary junction and medullary vasa recta; however, glomerular sclerosis was not observed. Fibrosis was correlated to focal tissue hypoxia as determined by immunohistochemical detection of tissue bound pimondazole. Conclusion. We conclude that there are significant histopathologic consequences, focused in the kidney, resulting from the daily administration of high doses of human recombinant TGF-β2, and we propose that selective vascular constriction with consequent tissue hypoxia is a contributing factor.