Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis

• Published in: American journal of physiology. Renal physiology Vol. 281; no. 5; pp. F909 - F919
• Main Authors: Dechow, C, Morath, C, Peters, J, Lehrke, I, Waldherr, R, Haxsen, V, Ritz, E, Wagner, J
• Format: Journal Article
• Language: English
• Published: United States 01.11.2001
• Subjects: Angiotensin II - biosynthesis; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Angiotensinogen - blood; Angiotensinogen - genetics; Animals; Antibodies - administration & dosage; Benzimidazoles - pharmacology; Blood Pressure; Kidney - chemistry; Kidney - metabolism; Kidney Glomerulus - pathology; Male; Nephritis - etiology; Nephritis - pathology; Nephritis - physiopathology; Peptidyl-Dipeptidase A - blood; Peptidyl-Dipeptidase A - genetics; Proto-Oncogene Proteins c-fos - biosynthesis; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid - genetics; Renin - blood; Renin - genetics; Renin-Angiotensin System - drug effects; RNA, Messenger - analysis; Tetrazoles - pharmacology; Thy-1 Antigens - immunology; Tretinoin - pharmacology
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.2001.281.5.F909

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.