Retinoic acid reduces glomerular injury in a rat model of glomerular damage

In the reaction of kidneys to injury, cytokine-driven proliferation plays a n important role and precedes the development of glomerulosclerosis. There is great interest in agents that may interfere with such proliferation. The refore, a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy1.1) was studied, and the effects of all-trans-retinoic acid (all- trans-RA) and isotretinoin, powerful antiproliferative and anti-inflammator y substances, on glomerular damage and cell proliferation were examined. Ve hicle-injected control rats were compared with rats treated with daily subc utaneous injections of 10 mg/kg body wt all-trans-RA or 40 mg/kg body wt is otretinoin (n = 9 to 11 per group), using either a pretreatment (days -2 th rough 8) or posttreatment (days +3 through +8) protocol, i.e., starting bef ore or after the induction of anti-Thy1.1 nephritis, respectively. All-tran s-RA prevented the BP increase evoked by anti-Thy1.1 (nnti-Thy1.1/vehicle, 112.2 +/- 4.8 mmHg; antiThy1.1/RA, 87.5 +/- 2.5 mmHg; P < 0.001). Treatment with all-trans-RA or isotretinoin produced a 70% decrease in the urinary a lbumin excretion rate (P < 0.02), Periodic acid-Schiff staining of saline-p erfused kidneys (day 8) revealed significantly fewer glomerular cells in RA -treated nephritic rats (anti-Thy1.1/ vehicle, 97 +/- 3.1 cells/glomerulus; anti-Thy1.1/RA, 80 +/- 4.4; P < 0.02; control/vehicle, 69 +/- 1.2). No dif ference was observed between all-trans-RA and isotretinoin treatment. The c apillary occlusion scores were significantly lower for the anti-Thy1.1/RA-t reated group (1.9 +/- 0.1) than for the anti-Thy1.1/vehicle-treated group ( 2.9 +/- 0.5, P < 0.001). In the anti-Thy1.1/vehicle-treated group, 11.9 +/- 1.1 glomerular cells were proliferating cell nuclear antigen-positive; how ever, in the anti-Thy1.1/RA-treated group, only 5.3 +/- 0.8 cells were prol iferating cell nuclear antigen-positive (P < 0.002; control, 2.2 +/- 0.2). Glomerular mitoses were reduced by 67% in the anti-Thy1.1/RA-treated group, compared with the anti-Thy1.1/control group (P < 0.002). Glomerular staini ng for platelet-derived growth factor B-chain was significantly reduced in anti-Thy1.1-treated nephritic rats in the presence of isotretinoin or all-t rans-PA, compared with the vehicle-treated group (P < 0.001). It is conclud ed that all-trans-RA limits glomerular proliferation, glomerular lesions, a nd albuminuria in an established model of renal damage. The findings point to retinoids as potential novel modulators of glomerular injury.