Renal fibrosis in mice treated with human recombinant transforming growth factor-beta2.
BACKGROUND
The biologic responses to transforming growth factor-beta (TGF-beta) suggest many potential therapeutic applications; however, in the only clinical trial to examine the effect of the systemic administration of a TGF-beta isoform, patients experienced significant but reversible declines in renal function. We studied the effects of administering human recombinant TGF-beta2 to adult mice.


METHODS
The effect of daily administration of TGF-beta2 on tissue vasoconstriction, tissue levels of endothelin and angiotensin II, tissue hypoxia, and renal fibrosis were examined.


RESULTS
Daily administration of TGF-beta2 at 10 or 100 microg/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 beta2. 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.


CONCLUSIONS
We conclude that there are significant histopathologic consequences, focused in the kidney, resulting from the daily administration of high doses of human recombinant TGF-beta2, and we propose that selective vascular constriction with consequent tissue hypoxia is a contributing factor.
Ledbetter
S
S
Genzyme Corporation, Framingham, Massachusetts 01701, USA. steve.ledbetter@genzyme.com
Kurtzberg
L
L
Doyle
S
S
Pratt
B M
BM
D000804:Angiotensin II / Q000032:analysis; D000818:Animals; D016319:Corrosion Casting; D019332:Endothelin-1 / Q000032:analysis; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007511:Ischemia / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000737:chemistry / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D011347:Procollagen / Q000032:analysis; D011994:Recombinant Proteins / Q000633:toxicity; D016212:Transforming Growth Factor beta / Q000633:toxicity*; D053781:Transforming Growth Factor beta2; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D011347:Procollagen; D011994:Recombinant Proteins; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000804:Angiotensin II