isotretinoin and Albuminuria

Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor beta1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin-angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cells, Cultured; Chronic Disease; Collagen Type V; Dermatologic Agents; Dose-Response Relationship, Drug; Gene Expression Regulation; Isotretinoin; Kidney Diseases; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta1

Retinoic acids, derivatives of vitamin A, act through retinoid receptors that are expressed in renal and immunocompetent cells (B and T cells; monocytes and macrophages). In experimental models of glomerulonephritis and renal interstitial disease, retinoids were shown to reduce both glomerular and tubular damage and inflammation. We therefore examined whether retinoids reduce cellular rejection and renal damage in a model of acute renal allograft rejection.. Kidneys of Fisher rats (F344, RT11v1) were orthotopically grafted to Lewis rats (RT11). Animals were killed 7 or 14 days after transplantation. Rats undergoing transplantation were treated with isotretinoin (13 cis-retinoic acid) at a low dose of 2 mg/kg body weight per day (LD isotretinoin) or at a high dose of 20 mg/kg body weight per day (HD isotretinoin) or with vehicle.. At day 14, albuminuria was reduced by approximately 70% (vehicle: 1.1+/-0.2 mg/24 hr vs. LD isotretinoin: 0.32+/-0.1 mg/24 hr; P<0.001). At days 7 and 14 serum creatinine levels were significantly higher in the vehicle-treated group than in the LD and HD isotretinoin-treated rats (P<0.05). Both LD and HD isotretinoin significantly reduced acute vascular injury compared with vehicle-treated rats (score at day 14: LD isotretinoin 20.1+/-5.1 vs. vehicle 57.8+/-9.9, P<0.01), acute glomerular injury (score: LD isotretinoin 6.8+/-1.0 vs. vehicle 10.6+/-0.9 P<0.05), and the number of glomerular monocytes and macrophages and cytotoxic T cells. Isotretinoin also significantly lessened tubulointerstitial damage, tubulointerstitial cell proliferation, and the number of cells infiltrating the tubulointerstitium.. Isotretinoin significantly ameliorated functional, vascular, glomerular, and tubulointerstitial lesions in acute graft rejection. Although the current study did not definitely eliminate the possibility that isotretinoin only delayed the rejection process, retinoic acid derivatives may provide a new approach in the treatment of acute rejection injury.

Topics: Albuminuria; Animals; Creatine; Graft Rejection; Immunohistochemistry; Isotretinoin; Kidney; Kidney Glomerulus; Kidney Transplantation; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew

Retinoids, derivatives of vitamin A, have strong anti-inflammatory and antiproliferative properties. We previously demonstrated that the pan-agonists all-transretinoic acid (RA) and isotretinoin (13-cis RA) alleviate renal damage in rat acute glomerulonephritis (GN) induced by anti-Thy-1.1 mAb OX-7.. The present study examined the effects of low dose and high dose treatment with isotretinoin in the chronic glomerulonephritis model, Thy-GN. Thy-GN was induced by a single intravenous injection of monoclonal antibody (mAb) 1-22-3 in uninephrectomized Wistar rats (N = 7 to 10 per group). Control and nephritic groups were treated with vehicle (veh), low dose isotretinoin (2 mg/kg body wt), or high dose isotretinoin (10 mg/kg body wt). The experiment was terminated 60 days after induction of Thy-GN.. In animals with Thy-GN, isotretinoin abrogated the increase in blood pressure and significantly reduced albuminuria. Glomerulosclerosis index, glomerular and interstitial cell counts, as well as the area of the interstitial space were significantly lower in nephritic rats treated with low and high dose isotretinoin compared to vehicle-treated nephritic controls. Treatment with isotretinoin also significantly reduced the number of glomerular and interstitial macrophages. The increase of transforming growth factor (TGF)-beta1, TGF receptor II and prepro-endothelin-1 gene expression in vehicle-treated nephritic rats was significantly attenuated by isotretinoin.. Treatment with isotretinoin significantly reduces glomerular and interstitial damage in rats with chronic glomerulonephritis as indicated by different functional and histological markers. Retinoids may provide a novel therapeutic option for the treatment of glomerulonephritis.

Topics: Albuminuria; Animals; Blood Pressure; Body Weight; Chronic Disease; Collagen Type I; Creatinine; Fibronectins; Gene Expression; Glomerulonephritis; Isotretinoin; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Rats; Rats, Wistar

ABSTRACT.: In the reaction of kidneys to injury, cytokine-driven proliferation plays an important role and precedes the development of glomerulosclerosis. There is great interest in agents that may interfere with such proliferation. Therefore, 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-inflammatory substances, on glomerular damage and cell proliferation were examined. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans-RA or 40 mg/kg body wt isotretinoin (n = 9 to 11 per group), using either a pretreatment (days -2 through 8) or posttreatment (days +3 through +8) protocol, i.e., starting before or after the induction of anti-Thy1.1 nephritis, respectively. All-trans-RA prevented the BP increase evoked by anti-Thy1.1 (anti-Thy1.1/vehicle, 112.2 +/- 4.8 mmHg; anti-Thy1.1/RA, 87.5 +/- 2. 5 mmHg; P < 0.001). Treatment with all-trans-RA or isotretinoin produced a 70% decrease in the urinary albumin excretion rate (P < 0. 02). Periodic acid-Schiff staining of saline-perfused 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 difference was observed between all-trans-RA and isotretinoin treatment. The capillary occlusion scores were significantly lower for the anti-Thy1.1/RA-treated 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; however, in the anti-Thy1.1/RA-treated group, only 5.3 +/- 0.8 cells were proliferating 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 staining for platelet-derived growth factor B-chain was significantly reduced in anti-Thy1.1-treated nephritic rats in the presence of isotretinoin or all-trans-RA, compared with the vehicle-treated group (P < 0.001). It is concluded that all-trans-RA limits glomerular proliferation, glomerular lesions, and albuminuria in an established model of renal damage. The findings point to retinoi

Topics: Albuminuria; Animals; Blood Pressure; Cell Count; Cell Division; Glomerulonephritis, Membranoproliferative; Isotretinoin; Kidney; Kidney Glomerulus; Macrophages; Male; Rats; Rats, Wistar; Tretinoin