Retinoic acid receptor [alpha] and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat

Byline: Matthias Schaier (1), Sabine Liebler (1), Kerstin Schade (1), Fujio Shimizu (1,2), Hiroshi Kawachi (1,2), Hermann-Joseph Grone (3), Roshantha Chandraratna (4), Eberhard Ritz (1), Juergen Wagner (1) Keywords: Chronic glomerulonephritis; Retinoids; Retinoid receptor expression 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 (RAR[alpha] agonist) or the retinoid X receptor specific agonist AGN 194204 (RXR agonist). Doses of either the RAR[alpha] 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 RAR[alpha] agonist or RXR agonist than with vehicle. The RAR[alpha] and RXR agonist significantly reduced the infiltration of the glomerulus by macrophages. The increase in glomerular TGF[beta]1 and prepro-ET.sub.1 gene expression in vehicle-treated nephritic rats was significantly attenuated by RAR[alpha] or RXR agonists. Glomerular expression of RXR[alpha] and RAR[alpha] receptor mRNA was significantly greater in vehicle-treated nephritic rats than in nonnephritic controls. Treatment with RAR[alpha] or RXR agonists tended to normalize retinoid-receptor gene expression. Our data indicate that both RAR[alpha] 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. Author Affiliation: (1) Department of Nephrology, University Hospital, University of Heidelberg, Bergheimer Strasse 56a, 69115, Heidelberg, Germany (2) Department of Nephrology, University of Niigata, Niigata, Japan (3) Department of Experimental Pathology, German Cancer Research Center, Heidelberg, Germany (4) Allergan Pharmaceuticals, Irvine, California, USA Article History: Registration Date: 04/11/2003 Received Date: 06/05/2003 Accepted Date: 30/10/2003 Online Date: 08/01/2004