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

We previously demonstrated that all-trans retinoic acid (RA) preserves glom erular 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: 14 79-1489, 2000). Because the renin-angiotensin system (RAS) contributes to r enal 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 bl ocker candesartan. Rats were pretreated for 3 days before injection of the OX-7 antibody and continued with treatment with either vehicle or daily inj ections of 10 mg/kg all-trans-RA only (study 1) or 10 mg/kg body wt all-tra ns-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 kid ney were unchanged, but renin mRNA was lower (P < 0.01). Renal and glomerul ar AT(1)-receptor gene and protein expression levels were higher in anti-Th y1.1 nephritic rats (P < 0.05). In the renal cortex of nephritic rats, pret reatment with all-trans-RA significantly reduced mRNAs of all the examined RAS components, but in the glomeruli it increased ACE gene and protein expr ession (P < 0.01). In nephritic rats, candesartan reduced the number of glo merular 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 t he renal RAS in anti-Thy1.1 nephritis by decreasing ANG II synthesis and re ceptor expression. The beneficial effect of retinoids may be explained, at least in part, by reduction of RAS activity.