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Effects of Retinoids on the TGF-ß System and Extracellular Matrix In J Am Soc Nephrol 12: 2300–2309, 2001 Effects of Retinoids on the TGF-␤ System and Extracellular Matrix in Experimental Glomerulonephritis CHRISTIAN MORATH,* CLAUDIUS DECHOW,* INGO LEHRKE,* VOLKER HAXSEN,* RUDIGER¨ WALDHERR,* JURGEN¨ FLOEGE,† EBERHARD RITZ,* and JURGEN¨ WAGNER* *Department of Nephrology, University of Heidelberg, Heidelberg, Germany; and †Department of Nephrology, University of Aachen, Aachen, Germany. Abstract. Transforming growth factor–␤1 (TGF-␤1) overex- compared with untreated animals (P Ͻ 0.025). Cortical expres- pression plays a key role in the glomerular accumulation of sion of TGF receptor II, but not receptor I gene expression, was extracellular matrix proteins in renal disease. Retinoids have significantly lower in animals treated with all-trans retinoic previously been shown to significantly limit glomerular dam- acid or isotretinoin (P Ͻ 0.05). In all-trans retinoic acid–treated age in rat experimental glomerulonephritis. Therefore, the ef- animals with Thy-GN, the increase of glomerular TGF-␤1 fects of all-trans retinoic acid and isotretinoin on the compo- protein (P Ͻ 0.008) and TGF-␤1(P Ͻ 0.025) and TGF nents of the TGF-␤ system and extracellular matrix proteins in receptor II mRNA (P Ͻ 0.015) was significantly less. Immu- anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle- nohistochemistry revealed less glomerular staining for TGF-␤1 injected control rats were compared with rats treated with daily and TGF receptor II in the presence of all-trans retinoic acid. subcutaneous injections of 10 mg/kg body wt all-trans retinoic TGF-␤1 immunostaining was not restricted to monocytes and acid or 40 mg/kg body wt isotretinoin (n ϭ 9 per group) either macrophages, as indicated by double-staining. Glomerular with a pretreatment (day Ϫ2 through 8) or posttreatment pro- staining for collagen IV and collagen III was less in animals tocol (day ϩ3 through 8), i.e., starting before or after induction treated with isotretinoin (P Ͻ 0.02 for both) in contrast to of Thy-GN, respectively. Urinary TGF-␤1 excretion was 60% all-trans retinoic acid, whereas fibronectin remained un- lower in all-trans retinoic acid–treated animals with Thy-GN changed. It was concluded that the beneficial effects of retin- (P Ͻ 0.025). The increase of cortical TGF-␤1 gene expression oids on glomerular damage are presumably due to a marked in Thy-GN rats was significantly attenuated with all-trans reduction in renal TGF-␤1 and TGF receptor II expression. retinoic acid and even more with isotretinoin treatment as Transforming growth factor–␤ (TGF-␤) is a prototype of a The role of retinoids, derivatives of vitamin A, in embryogen- profibrogenic cytokine (1). TGF-␤ stimulates transcription of esis (including renal development) has been studied in detail many extracellular matrix genes in renal cells (2,3). TGF-␤ (12,13). Little is known, however, about the renal effects of these inhibits extracellular matrix turnover by reducing collagenase compounds. Retinoids exert strong antiproliferative and anti-in- production and by stimulation of tissue inhibitor metallopro- flammatory effects. They act via retinoid acid and retinoid X teinase expression (4). In several models of renal disease, receptor subtypes, which belong to the steroid supergene family TGF-␤ has been implicated as a primary mediator of cell (14). These receptors influence gene expression either via retinoid growth and accumulation of extracellular matrix, e.g., diabetic responsive cis-acting elements or via modulation of transcription nephropathy, experimental glomerulonephritis, or unilateral factors such as AP-1, Nf␬B, or GATA (15–19). ureteral obstruction (5,6). Renal TGF-␤1 gene expression is We had demonstrated that retinoids attenuate glomerular markedly elevated in anti–Thy-nephritis or anti-thymocyte se- damage in anti-Thy1.1-nephritis (Thy-GN) (20), as indicated rum nephritis (7–9). Matrix expansion was less when TGF-␤1 by preservation of renal function, less albuminuria, and lower was antagonized by neutralizing antibodies or antisense oligo- capillary occlusion score. It has been suggested that in this nucleotides (10,11). model TGF-␤ is crucial for matrix expansion and fibrosis. We, therefore, decided to examine the effects of retinoids on the renal TGF-␤ system and the expression of collagen III, IV, and Received February 23, 2000. Accepted May 9, 2001. Dr. Richard Glassock served as the Guest Editor and supervised the review and fibronectin in Thy-GN in the rat. We compared non-nephritic final disposition of this manuscript. control rats with Thy-GN animals that were treated with all- Correspondence to Dr. Ju¨rgen Wagner, Department of Nephrology, University trans retinoic acid, isotretinoin, or vehicle. Hospital, Universitiy of Heidelberg, Bergheimerstrasse 56a, D-69115 Heidel- berg, Germany. Phone: ϩ49 6221 91120; Fax: ϩ49 6221 16 24 76. E-mail: [email protected] Materials and Methods 1046-6673/1211-2300 Animal Studies Journal of the American Society of Nephrology Thy-GN was induced by a single injection of OX-7, a monoclonal Copyright © 2001 by the American Society of Nephrology antibody against the Thy1.1-antigen (European Collection of Animal J Am Soc Nephrol 12: 2300–2309, 2001 Effects of Retinoids on TGF in Nephritis 2301 Cell Cultures, Salisbury, UK). Male pair-fed Wistar rats (Charles 94°C for 1 min, annealing at 55°C for 1 min, and extension at 72°C River, Sulzfeld, Germany), weighing 180 to 200 g, were used for all for 1 min carried out 30 times for TGF-␤1, 28 times for TGF receptor studies. In a first experiment (the pretreatment protocol), two groups II, and 32 times for TGF receptor I (subtype R4). In all experiments, of 18 animals each were treated with daily subcutaneous injections of possible contamination with genomic DNA was excluded by PCR 10 mg/kg body wt all-trans retinoic acid (Sigma-Aldrich Chemie amplification in the absence of reverse transcriptase. Amplification GmbH, Steinheim, Germany) dissolved in arachis oil and 5% dimeth- products were separated by agarose gel electrophoresis and then ylsulfoxide or arachis oil and dimethylsulfoxide as vehicle control, digitized by use of a gel documentation system (Intas, Go¨ttingen, respectively. Two days later, animals received by injection into the Germany) and NIH Image (National Institutes of Health, Bethesda, tail vein either 1 mg/kg body wt OX-7 (n ϭ 9) or phosphate-buffered MD). The ratio between the optical density of the endogenous cDNA saline (PBS) as control (n ϭ 9), respectively. The experiment was and the optical density of the mutant DNA was determined. Each terminated 8 d after injection of the antibody. sample was measured in three individual PCR assays for each gene. In a second experiment (the posttreatment protocol), animals were first given OX-7 or PBS and then, 2 d later, 10 mg/kg body wt Enzyme-Linked Immunosorbent Assay for TGF-␤1 all-trans retinoic acid or vehicle. This experiment included two further For enzyme-linked immunosorbent assay (ELISA), glomeruli were experimental groups that were treated with daily subcutaneous injec- isolated and centrifuged in PBS. The pellet was resuspended in 50 ␮l tions of 40 mg/kg body wt isotretinoin (13-cis retinoic acid; Hoffmann of Laemmli buffer 1 (33% 0.5 mM Tris-HCl [pH 6.8], 66% SDS LaRoche, Basel, Switzerland) dissolved in arachis oil and 5% dimeth- 10%). Protein was isolated by three cycles of freeze and thaw. The ylsulfoxide. Each group was composed of nine animals. The experi- supernatant was recovered after centrifugation. The protein concen- ment was terminated 8 d after injection of the antibody. tration was determined according to the method of Bradford (22). BP was determined on day 8 by tail-cuff plethysmography under TGF-␤1 in glomeruli and urine was measured after acid activation light ether anesthesia. For determination of TGF-␤1 in urine, rats were by use of a commercially available inhibitory ELISA kit (Immundi- placed in metabolic cages and urine was collected for 24 h. The agnostik, Bensheim, Germany), according to the manufacturer’s in- experiment was terminated by injection of 5 mg/kg body wt Xylazin structions. Each sample was measured in quadruplicate. intramuscularly (BayerVital, Leverkusen, Germany) and 100 mg/kg body wt Ketamin 10% intramuscularly (WDT, Garbsen, Germany). Kidneys were perfused with normal saline at 37°C that contained 0.5 Immunohistochemistry g/L procaine hydrochloride at a pressure of 110 mm Hg. Glomeruli Saline-perfused 4-␮m slices of renal tissue were fixed in 10% were isolated by a fractionated sieving technique. The yield and the buffered formaline (TGF-␤1, TGF receptor II, and Ki-M2R) or purity of isolated glomeruli at each time point were comparable methyl Carnoy’s solution (fibronectin and collagen IV and III) and between groups (purity Ͼ90%). were processed by a direct or indirect immunoperoxidase technique. Primary antibodies included an affinity-purified IgG fraction of a RNA Isolation and Reverse Transcription polyclonal rabbit anti-rat fibronectin (Chemicon, Temecula, CA), a biotinylated IgG fraction of a polyclonal goat anti-mouse type IV and The Trizol (Life Technologies, Paisley, UK) method was used for type III collagen (Southern Biotech, Birmingham, AL), an IgG frac- RNA isolation, according to the manufacturer’s recommendations. tion of a polyclonal rabbit anti-rat TGF-␤1 and TGF receptor II (Santa Samples were checked for degradation of total RNA on 1% agarose Cruz Biotechnology, Santa Cruz, CA), and a monoclonal mouse gel. RNA concentrations were determined by spectrophotometric anti-rat pan-macrophage antibody Ki-M2R (DPC Biermann, Bad measurements at wavelengths of 260/280 nm. Reverse transcription Nauheim, Germany). was performed as described elsewhere (21). For each sample, reverse Negative controls consisted of substitution of the primary antibody transcription was carried out three times and the resulting cDNA was with equivalent concentrations of an irrelevant murine monoclonal pooled.
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