Kidneys of Alb/TGF-beta1 transgenic mice are deficient in retinoic acid and exogenous retinoic acid shows dose-dependent toxicity.
BACKGROUND
Alb/TGF-beta(1) transgenic mice overexpress active transforming growth factor-beta(1) (TGF-beta(1)) in the liver, leading to increased circulating levels of the cytokine and progressive renal fibrosis. This study was designed to explore if exogenous all-trans retinoic acid (tRA) prevents renal fibrosis in this animal model.


METHODS
The retinoid profile in kidney and liver of wild-type and Alb/TGF-beta(1) transgenic mice was examined by high-performance liquid chromatography and slow-release pellets containing different amounts of tRA were implanted subcutaneously to treat the Alb/TGF-beta(1) transgenic mice, starting at 1 week of age; mice were sacrificed 2 weeks later.


RESULTS
Kidneys of 3-week-old wild-type mice had abundant tRA, which was completely absent in kidneys of the transgenic mice. Low doses of tRA (6-10.7 mg/kg/day) failed to affect renal fibrosis although it tended to suppress the mRNA expression of some molecular markers of fibrosis and retinal dehydrogenase 2 (RALDH2), a gene encoding a key tRA-synthesising enzyme. These tendencies disappeared, mortality tended to increase and RALDH2 and connective tissue growth factor (CTGF) mRNAs significantly increased in the medium-dose group (12.7-18.8 mg/kg/day). High doses (20.1-27.4 mg/kg/day) showed even higher toxicity with increased renal fibrosis and significant mortality.


CONCLUSIONS
Alb/TGF-beta(1) transgenic mice are characterised by depletion of endogenous renal tRA. Exogenous tRA dose-dependently increases mortality and kidney fibrosis, which is associated with dose-dependent regulation of renal RALDH2 and CTGF mRNA expression.
Xu
Qihe
Q
Department of Renal Medicine, King's College London, London, UK. qihe.xu@kcl.ac.uk
Hendry
Bruce M
BM
Maden
Malcolm
M
Lu
Huiyan
H
Wong
Yuen Fei
YF
Rankin
Alexandra C
AC
Noor
Mazhar
M
Kopp
Jeffrey B
JB
D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism* / Q000633:toxicity*
C526318:CCN2 protein, mouse; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D014212:Tretinoin