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Articles in PresS, published online ahead of print October 30, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.00026.2001
Submitted on February 2, 2001
Accepted on October 12, 2001
1 Nephrology, University of Heidelberg, Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: juergen.wagner{at}urz.uni-heidelberg.de.
Retinoids are potent anti-proliferative 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 now examined the effects of synthetic retinoid-receptor-specific agonists i) to identify common and receptor subtype specific pathways in this model and ii) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared to rats treated with daily subcutaneous injections of agonists specific for retinoid-A-receptor (Ro137410) and retinoid-X-receptor (Ro257386), and the complex anti-activator protein-1 active retinoid BMS453 seven days after induction of anti-Thy1.1-nephritis (n=7-9 per group). The different retinoids lowered with comparable efficacy glomerular ET-1, ETA and ETB receptor gene expression in control and nephritic rats. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests down-regulation of transactivating factors required for endothelin expression. The different retinoids were similar in their action on glomerular capillary occlusion score, number of total glomerular cells and glomerular infiltrating macrophage count. They did, however, differ in their ability to normalize blood pressure (Ro257386>BMS453>Arotinoid), albuminuria (BMS453>Ro257386>Arotinoid) and creatinine clearance (Arotinoid>BMS453> Ro257386). 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. Both retinoid X and A receptor-specific pathways are apparently involved in the anti-proliferative, anti-inflammatory and anti-endothelin action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.
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