ABSTRACT
Retinoids, derivatives of vitamin A, inhibit mesangial cell proliferation, glomerular inflammation, and extracellular matrix deposition in acute anti-Thy1.1 glomerulonephritis (Thy-GN) of the rat. We examined a model, chronic mesangioproliferative Thy-GN (MoAb 1-22-3), which is more akin to human disease. Treatment started on day 23 when Thy-GN had already been established. Nonnephritic control and Thy-GN rats were treated orally for 67 days with vehicle or with two doses of either the retinoic acid receptor alpha-specific agonist AGN 195183 (RARalpha agonist) or the retinoid X receptor specific agonist AGN 194204 (RXR agonist). Doses of either the RARalpha or the RXR agonist significantly reduced albuminuria and normalized blood pressure during the course of treatment. The glomerulosclerosis index, glomerular cell and interstitial cell counts, and area of the interstitial space were significantly lower in nephritic rats treated with the RARalpha agonist or RXR agonist than with vehicle. The RARalpha and RXR agonist significantly reduced the infiltration of the glomerulus by macrophages. The increase in glomerular TGFbeta1 and prepro-ET(1) gene expression in vehicle-treated nephritic rats was significantly attenuated by RARalpha or RXR agonists. Glomerular expression of RXRalpha and RARalpha receptor mRNA was significantly greater in vehicle-treated nephritic rats than in nonnephritic controls. Treatment with RARalpha or RXR agonists tended to normalize retinoid-receptor gene expression. Our data indicate that both RARalpha agonists and RXR agonists reduce renal damage in rats with established chronic glomerulonephritis. Receptor-specific retinoids may provide a novel therapeutic approach for the treatment of chronic glomerulonephritis.
Subject(s)
Fatty Acids, Unsaturated/therapeutic use , Glomerulonephritis, Membranoproliferative/drug therapy , Receptors, Retinoic Acid/agonists , Retinoids/therapeutic use , Tetrahydronaphthalenes/therapeutic use , Transcription Factors/agonists , Albuminuria/metabolism , Animals , Biomarkers/analysis , Blood Pressure/drug effects , Chronic Disease , Creatinine/metabolism , Creatinine/urine , Gene Expression/drug effects , Glomerulonephritis, Membranoproliferative/metabolism , Glomerulonephritis, Membranoproliferative/pathology , Isoantibodies/toxicity , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/therapy , Kidney Glomerulus/pathology , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptors, Retinoic Acid/genetics , Retinoic Acid Receptor alpha , Retinoid X Receptors , Retinoids/metabolism , Tetrahydronaphthalenes/pharmacology , Transcription Factors/geneticsABSTRACT
Retinoids are potent antiproliferative and anti-inflammatory compounds. We previously demonstrated that the natural pan-agonists all-trans retinoic acid (RA) and 13-cis RA efficiently preserve renal structure and function in rat mesangioproliferative glomerulonephritis. We examine effects of synthetic retinoid receptor-specific agonists 1) to identify common and receptor subtype-specific pathways in this model and 2) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of agonists specific for retinoid A (Ro-137410) and retinoid X (Ro-257386) receptors and the complex anti-activator protein-1 active retinoid BMS-453 7 days after induction of anti-Thy1.1 nephritis (n = 7-9/group). The different retinoids lowered glomerular ET-1 and ET type A and B receptor gene expression in control and nephritic rats with comparable efficacy. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests downregulation of transcription factors required for ET expression. The different retinoids were similar in their action on the glomerular capillary occlusion score, number of total glomerular cells, and glomerular infiltrating macrophage count. They differed in their ability to normalize blood pressure (Ro-257386 > BMS-453 > arotinoid), albuminuria (BMS-453 > Ro-257386 > arotinoid), and creatinine clearance (arotinoid > BMS-453 > Ro-257386). No signs of toxicity were observed. We conclude that all retinoid agonists with different subtype specificity are highly efficient in reducing renal damage and proliferation of mesangial cells. Retinoid X and A receptor-specific pathways are apparently involved in the antiproliferative, anti-inflammatory, and anti-ET action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.