6-ketoprostaglandin-f1-alpha and Lupus-Nephritis

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cross-Over Studies; Enzyme Inhibitors; Female; Humans; Imidazoles; Indomethacin; Lupus Nephritis; Male; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been described as being less toxic than conventional immunosuppressants, and it was effective in preventing progressive nephritis in lupus mice. Our study evaluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with established disease. We also examined the combination of MMF with a selective cyclooxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A2 (TXA2) in lupus nephritis.. Four groups of NZB/W mice (N = 30 each group), starting at five months of age, were given daily by gavage the following: vehicle, MMF 60 mg/kg, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months.. MMF or DFU alone partially delayed the onset of proteinuria compared with vehicle. Combined therapy was significantly (P < 0.05) more effective than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the vehicle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the vehicle group. Renal damage was also limited, but to a greater extent in mice given the combined therapy. In untreated mice, renal COX-2 mRNA expression was up-regulated, and generation of TXB(2), the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB(2) production, confirming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha) and prostaglandin E(2) (PGE(2)) were not affected substantially.. These results offer a strong case for exploring the possibility that in humans MMF combined with COX-2 inhibitors has a role in the treatment options for lupus nephritis. This combined drug therapy may be at least as effective as steroids but without the obvious nephrotoxicity of the latter.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Furans; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Isoenzymes; Kidney; Lupus Nephritis; Lymphocyte Count; Lymphocyte Subsets; Membrane Proteins; Mice; Mice, Inbred NZB; Mycophenolic Acid; Prostaglandin-Endoperoxide Synthases; Proteinuria; Spleen; Survival Rate; Thromboxane B2

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Complement C3; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Extracellular Matrix Proteins; Female; Fluorescent Antibody Technique; Glomerular Mesangium; Immunoglobulin G; Indomethacin; Kidney Glomerulus; Ligation; Lupus Nephritis; Mice; Thromboxane B2; Ureter; Ureteral Obstruction

Abnormalities of prostanoid metabolism, which may affect renal function, were studied in lupus nephritis. The subjects were 31 patients with lupus nephritis, ten with non-renal SLE, and four with renal, non-SLE collagen disease. Urinary levels of various prostanoids, thromboxane B2(TXB2), 11-dehydro-TXB2, 6-keto-PGF1 alpha,2,3-dinor-6-keto-PGF1 alpha and PGE2, and plasma level of 11-dehydro-TXB2, were determined. The effects of four days' dosing of a selective thromboxane A2 (TXA2) synthetase inhibitor, DP-1904 (DP), on prostanoid metabolism, were also studied. Urinary excretion of TXB2, which reflects the renal production of TXA2, was significantly increased in patients with lupus nephritis as compared with non-renal SLE (p < 0.05). The urinary TXB2/6-keto-PGF1 alpha ratio was also increased in lupus nephritis as compared with non-renal SLE or healthy controls (p < 0.01), indicating a prostanoid imbalance, which may lead to impaired renal function and subsequent pathology. The urinary TXB2/6-keto-PGF1 alpha ratio in these lupus nephritis patients showed negative correlations with Ccr and positive correlations with anti-DNA antibody titer (p < 0.001). DP was administered orally (400 mg/day, given in two divided doses) for four days to eight lupus nephritis patients. The urinary excretion of TXB2 and urinary TXB2/6-keto-PGF1 alpha ratio were decreased after one to two days of treatment in all patients. An increase in creatinine clearance used as a measure of renal function was observed in four of eight patients. Furthermore, no side effects were elicited during the four days of treatment. The conclusion reached were that the abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function through hemodynamic mediation, and that the deviated metabolism was reversible and, at least partially, corrected by a TXA2 synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Enzyme Inhibitors; Female; Humans; Imidazoles; Kidney Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prostaglandins; Reference Values; Regression Analysis; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The glomerular functional and structural changes in a murine model (MRL-lpr/lpr) of progressive lupus nephritis were studied. Animals were grouped into three age categories. (I, 14 wk; II, 20 wk; and III, 26 wk). GFR fell with age (257 +/- 43, 178 +/- 50, and 150 +/- 40 microL/min for Groups I through III, respectively). Similarly, the ultrafiltration coefficient (Kf) measured on isolated glomeruli fell with time (0.030 +/- 0.006, 0.023 +/- 0.006, and 0.013 +/- 0.002 nL/s/mm Hg, respectively). Both indomethacin and a selective thromboxane receptor antagonist L-670,596 significantly improved GFR in Group II animals to values seen in Group I animals. Neither agent had any effect to increase GFR in older group III animals. L-670,596 had no effect on Kf in Group II or III animals. Glomerular morphometric evaluation demonstrated a progressive rise in glomerular tuft volume, mesangial matrix expansion, proliferation in cells, and a reduction in open capillary loops and epithelial filtration slits with age. However, because of the increase in glomerular volume, calculated surface area remained well preserved over the three respective groups (61 +/- 18, 76 +/- 15, and 71 +/- 13 microns2 x 10(3)). Therefore, the fall in Kf is likely due to a fall in hydraulic permeability (Lp). The ultrastructural component of the glomerular capillary wall that correlated best with Lp was the epithelial filtration slit number per micrometer of glomerular basement length (r = 0.73; P < 0.0001), which suggests that the structural correlate Kf is in the filtration slit length (FSL). Despite the cell proliferation and mesangial matrix expansion in early disease (Group II), the overall FSL remains stable because of a slight increase in filtration surface area and a slight reduction in epithelial slits per micrometer of glomerular basement membrane. The fall in GFR appears to be hemodynamically mediated by thromboxane A2. In older Group III animals, the fall in GFR appears to be due to a 40% reduction in FSL rather than being hemodynamically based. Thus, the early improvement in function with pharmacological agents is deceptive because considerable disease may be present because of adaptive structural changes. Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Carbazoles; Female; Glomerular Filtration Rate; Hematocrit; Indomethacin; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Organ Size; Renal Circulation; Thromboxane B2

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Alprostadil; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Iloprost; Lupus Nephritis; Mice; Mice, Inbred NZB; Mice, Inbred Strains; Nephritis; Proteinuria; Thromboxane B2; Vasodilator Agents