Kidneys of Alb/TGF-beta1 Transgenic Mice Are Deficient in Retinoic Acid and Exogenous Retinoic Acid Shows Dose-dependent Toxicity

Overview

Journal Nephron Exp Nephrol

Publisher Karger

Specialties Biology
Nephrology

Date 2010 Jan 30

PMID 20110732

Citations 7

Authors

Qihe Xu

Bruce M Hendry

Malcolm Maden

Huiyan Lu

Yuen Fei Wong

Alexandra C Rankin

Mazhar Noor

Jeffrey B Kopp

Affiliations

Soon will be listed here.

Abstract

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.

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References

Lateef H, Stevens M, Varani J . All-trans-retinoic acid suppresses matrix metalloproteinase activity and increases collagen synthesis in diabetic human skin in organ culture. Am J Pathol. 2004; 165(1):167-74. PMC: 1618544. DOI: 10.1016/S0002-9440(10)63285-3. View

Lopez-Bermejo A, Buckway C, Devi G, Hwa V, Plymate S, Oh Y . Characterization of insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 1, 2, and 3 in human prostate epithelial cells: potential roles for IGFBP-rP1 and 2 in senescence of the prostatic epithelium. Endocrinology. 2000; 141(11):4072-80. DOI: 10.1210/endo.141.11.7783. View

Daly T, Weston W . Retinoid effects on fibroblast proliferation and collagen synthesis in vitro and on fibrotic disease in vivo. J Am Acad Dermatol. 1986; 15(4 Pt 2):900-2. DOI: 10.1016/s0190-9622(86)70248-x. View

Cash D, Gates P, Imokawa Y, Brockes J . Identification of newt connective tissue growth factor as a target of retinoid regulation in limb blastemal cells. Gene. 1998; 222(1):119-24. DOI: 10.1016/s0378-1119(98)00478-8. View

Cao Z, Flanders K, Bertolette D, Lyakh L, Wurthner J, Parks W . Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Blood. 2002; 101(2):498-507. DOI: 10.1182/blood-2002-05-1549. View

Pendaries V, Verrecchia F, Michel S, Mauviel A . Retinoic acid receptors interfere with the TGF-beta/Smad signaling pathway in a ligand-specific manner. Oncogene. 2003; 22(50):8212-20. DOI: 10.1038/sj.onc.1206913. View

Okuno M, Moriwaki H, Imai S, Muto Y, Kawada N, Suzuki Y . Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells. Hepatology. 1997; 26(4):913-21. DOI: 10.1053/jhep.1997.v26.pm0009328313. View

Davis B, Kramer R, Davidson N . Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production. J Clin Invest. 1990; 86(6):2062-70. PMC: 329845. DOI: 10.1172/JCI114943. View

Shimo T, Koyama E, Sugito H, Wu C, Shimo S, Pacifici M . Retinoid signaling regulates CTGF expression in hypertrophic chondrocytes with differential involvement of MAP kinases. J Bone Miner Res. 2005; 20(5):867-77. DOI: 10.1359/JBMR.041235. View

10.

Yuen P, Dunn S, Miyaji T, Yasuda H, Sharma K, Star R . A simplified method for HPLC determination of creatinine in mouse serum. Am J Physiol Renal Physiol. 2004; 286(6):F1116-9. DOI: 10.1152/ajprenal.00366.2003. View

11.

Redlich C, DeLisser H, Elias J . Retinoic acid inhibition of transforming growth factor-beta-induced collagen production by human lung fibroblasts. Am J Respir Cell Mol Biol. 1995; 12(3):287-95. DOI: 10.1165/ajrcmb.12.3.7873195. View

12.

Federspiel S, Dimari S, Howe A, Haralson M . Extracellular matrix biosynthesis by cultured fetal rat lung epithelial cells. IV. Effects of chronic exposure to retinoic acid on growth, differentiation, and collagen biosynthesis. Lab Invest. 1991; 65(4):441-50. View

13.

La P, Morgan T, Sykes S, Mao H, Schnepp R, Petersen C . Fusion proteins of retinoid receptors antagonize TGF-beta-induced growth inhibition of lung epithelial cells. Oncogene. 2003; 22(2):198-210. DOI: 10.1038/sj.onc.1206100. View

14.

Wu L, Ishikawa Y, Nie D, Genge B, Wuthier R . Retinoic acid stimulates matrix calcification and initiates type I collagen synthesis in primary cultures of avian weight-bearing growth plate chondrocytes. J Cell Biochem. 1997; 65(2):209-30. DOI: 10.1002/(sici)1097-4644(199705)65:2<209::aid-jcb7>3.0.co;2-y. View

15.

Achkar C, Derguini F, Blumberg B, Langston A, Levin A, Speck J . 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors. Proc Natl Acad Sci U S A. 1996; 93(10):4879-84. PMC: 39373. DOI: 10.1073/pnas.93.10.4879. View

16.

Xu Q, Lucio-Cazana J, Kitamura M, Ruan X, Fine L, Norman J . Retinoids in nephrology: promises and pitfalls. Kidney Int. 2004; 66(6):2119-31. DOI: 10.1111/j.1523-1755.2004.66002.x. View

17.

Mozes M, Bottinger E, Jacot T, Kopp J . Renal expression of fibrotic matrix proteins and of transforming growth factor-beta (TGF-beta) isoforms in TGF-beta transgenic mice. J Am Soc Nephrol. 1999; 10(2):271-80. DOI: 10.1681/ASN.V102271. View

18.

Sinha P, Clements V, Ostrand-Rosenberg S . Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol. 2005; 174(2):636-45. DOI: 10.4049/jimmunol.174.2.636. View

19.

Blush J, Lei J, Ju W, Silbiger S, Pullman J, Neugarten J . Estradiol reverses renal injury in Alb/TGF-beta1 transgenic mice. Kidney Int. 2004; 66(6):2148-54. DOI: 10.1111/j.1523-1755.2004.66005.x. View

20.

Kopp J, Factor V, Mozes M, Nagy P, Sanderson N, Bottinger E . Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest. 1996; 74(6):991-1003. View