Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat.
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.
Schaier
Matthias
M
Department of Nephrology, University Hospital, University of Heidelberg, Bergheimer Strasse 56a, 69115, Heidelberg, Germany. matthias.schaier@med.uni-heidelberg.de
Liebler
Sabine
S
Schade
Kerstin
K
Shimizu
Fujio
F
Kawachi
Hiroshi
H
Grone
Hermann-Joseph
HJ
Chandraratna
Roshantha
R
Ritz
Eberhard
E
Wagner
Juergen
J
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D003404:Creatinine / Q000378:metabolism / Q000652:urine; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007518:Isoantibodies / Q000633:toxicity; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics
C430898:AGN 194204; C492393:AGN 195183; D015415:Biomarkers; D005231:Fatty Acids, Unsaturated; D007518:Isoantibodies; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C035678:anti-Thy antibody; D003404:Creatinine