title: Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis.
abstract: We previously demonstrated that all-trans retinoic acid (RA) preserves glomerular structure and function in anti-Thy1.1 nephritis (Wagner J, Dechow C, Morath C, Lehrke I, Amann K, Floege J, and Ritz E. J Am Soc Nephrol 11: 1479-1489, 2000). Because the renin-angiotensin system (RAS) contributes to renal damage, we 1) studied retinoid-specific effects on its components and 2) compared the effects of all-trans-RA with those of the AT(1)-receptor blocker candesartan. Rats were pretreated for 3 days before injection of the OX-7 antibody and continued with treatment with either vehicle or daily injections of 10 mg/kg all-trans-RA only (study 1) or 10 mg/kg body wt all-trans-RA, 1 mg/kg candesartan, or both (study 2) for an additional 7 days. The blood pressure increase observed in anti-Thy1.1 nephritic rats was equally normalized by all-trans-RA and candesartan (P < 0.05). In nephritic rats, mRNAs of angiotensinogen and angiotensin-converting enzyme (ACE) in the kidney were unchanged, but renin mRNA was lower (P < 0.01). Renal and glomerular AT(1)-receptor gene and protein expression levels were higher in anti-Thy1.1 nephritic rats (P < 0.05). In the renal cortex of nephritic rats, pretreatment with all-trans-RA significantly reduced mRNAs of all the examined RAS components, but in the glomeruli it increased ACE gene and protein expression (P < 0.01). In nephritic rats, candesartan reduced the number of glomerular cells and mitoses (P < 0.05) less efficiently than all-trans-RA (P < 0.01). Both substances reduced cellular proliferation (proliferating cell nuclear antigen) significantly (P < 0.05). No additive effects were noted when both compounds were combined. In conclusion, all-trans-RA influences the renal RAS in anti-Thy1.1 nephritis by decreasing ANG II synthesis and receptor expression. The beneficial effect of retinoids may be explained, at least in part, by reduction of RAS activity.
authors.affiliation: Division of Nephrology, University of Heidelberg, D-69115, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Dechow
authors.forename: C
authors.initials: C
authors.lastname: Morath
authors.forename: J
authors.initials: J
authors.lastname: Peters
authors.forename: I
authors.initials: I
authors.lastname: Lehrke
authors.forename: R
authors.initials: R
authors.lastname: Waldherr
authors.forename: V
authors.initials: V
authors.lastname: Haxsen
authors.forename: E
authors.initials: E
authors.lastname: Ritz
authors.forename: J
authors.initials: J
authors.lastname: Wagner
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D009393:Nephritis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012083:Renin / Q000097:blood / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000906:Antibodies; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D013777:Tetrazoles; D018800:Thy-1 Antigens; D000808:Angiotensinogen; D000804:Angiotensin II; D014212:Tretinoin; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C081643:candesartan