Human renal mesangial cells are a target for the anti-inflammatory action of 9-cis retinoic acid.
Mesangial cells play an active role in the inflammatory response to glomerular injury. We have studied in cultured human mesangial cells (CHMC) several effects of 9-cis retinoic acid (9-cRA), an activator of both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). 9-cRA inhibited foetal calf serum-induced CHMC proliferation. It also prevented CHMC death induced by the inflammatory mediator H(2)O(2). This preventive effect was not due to any increase in H(2)O(2) catabolism and it persisted even when both catalase and glutathione synthesis were inhibited. Finally, 9-cRA diminished monocyte adhesion to FCS-stimulated CHMC. Interestingly, the retinoid also inhibited in FCS-stimulated cells the protein expression of two mesangial adhesion molecules, fibronectin and osteopontin, but it did not modify the protein expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. All major RARs and RXRs isotypes were expressed in CHMC regardless of the presence or absence of 9-cRA. Transcripts to RAR-alpha, RAR-beta and RXR-alpha increased after incubation with 9-cRA whereas RXR-gamma was inhibited, suggesting a major role for RARs and RXRs in 9-cRA-anti-inflammatory effects. 9-cRA was toxic only at 50 microM (a concentration 50 - 5000 times higher than required for the effects above). Cell death occurred by apoptosis, whose onset was associated with a pronounced increase in catalase activity and reduced glutathione content, being more effectively induced by all-trans retinoic acid. Modulation of the oxidant/antioxidant balance failed to inhibit apoptosis. We conclude that mesangial cells might be a target for the treatment of inflammatory glomerulopathies with 9-cRA.
Manzano
V M
VM
Department of Physiology, University of Alcala, Alcalá de Henares, Madrid, Spain.
Muñoz
J C
JC
Jiménez
J R
JR
Puyol
M R
MR
Puyol
D R
DR
Kitamura
M
M
Cazaña
F J
FJ
D000328:Adult; D000077556:Alitretinoin; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D009000:Monocytes / Q000166:cytology; D053495:Osteopontin; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D012795:Sialoglycoproteins / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D000893:Anti-Inflammatory Agents; D005353:Fibronectins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D053495:Osteopontin; D018799:Intercellular Adhesion Molecule-1; D000077556:Alitretinoin; D014212:Tretinoin; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione