Expression of platelet-derived growth factor in lupus nephritis in MRL/MpJ-1pr/1pr mice.

Platelet-derived growth factor (PDGF) plays an important role in the pathogenesis of mesangial proliferative glomerulonephritis. We examined PDGF expression and glomerular changes in lupus nephritis-prone MRL/MpJ-1pr/1pr (MRL/1) mice. The total number of nuclei per glomerular section and blood urea nitrogen (BUN) level were significantly increased in MRL/1 mice aged 20 weeks compared to those aged 8 weeks. A positive correlation existed between numbers of PDGF beta-chain-positive cells and glomerular cells in MRL/1 mice (r = 0.77, p < 0.01). The BUN level did not differ among MRL/MP-+2 (MRL/n) mice of different ages, but the glomerular cell number increased modestly with age. At the age of 20 weeks, the incidence of crescent formation per kidney tissue ranged from 9 to 32% (mean 19%) in MRL/1 mice but was 0 in MRL/n mice. PDGF beta-chain protein was expressed in the mesangium and crescents in 20-week-old MRL/1 mice but was expressed rarely in the glomeruli of MRL/n mice. These results suggest that the PDGF beta-chain plays an important role in glomerular cell proliferation and crescent formation in murine lupus nephritis.

Glomerulosclerosis in the rat induced by repeated immune-mediated mesangial cell injury.

Glomerulosclerosis is a common feature of progressive glomerular injury. We investigated whether experimental glomerulosclerosis could be induced by repeated immunologic injury to mesangial cells. Chronic mesangial proliferative glomerulonephritis (GN) was induced by repeated injections of polyclonal antibody directed against the Thy 1 antigen present on the mesangial cell membrane. An intravenous injection of anti-Thy 1 serum (ATS) was given weekly to 18 male Wistar rats, which were sacrificed at weeks 2, 4 and 6 after induction of GN. Blood urea nitrogen and serum creatinine were significantly elevated in rats with anti-Thy 1 nephritis at weeks 4 and 6 compared to normal rats. Progressive expansion of the mesangial matrix with diffuse sclerosis was observed at weeks 4 and 6 by silver methenamine staining. Ultrastructurally there was a prominent rough endoplasmic reticulum in the mesangial cells and collagenous fibrils in an expanded mesangial matrix. Immunohistochemical staining revealed a marked increase in type IV collagen and laminin in the mesangium at weeks 4 and 6. Thus, repeated immunologic injury restricted to the mesangium may result in the accumulation of extracellular matrix and the development of glomerulosclerosis. These studies emphasize the importance of the mesangial cell in progressive glomerular injury.

Effect of a novel immunosuppressant, FK506, on spontaneous lupus nephritis in MRL/MpJ-lpr/lpr mice.

We evaluated the effect of the novel immunosuppressive agent, FK506, which is known to inhibit T cell immunity, on the development of lupus nephritis in MRL/MpJ-lpr/lpr (MRL/l) mice. FK506 was administered subcutaneously (1 mg/kg body weight) from 12 to 20 weeks of age in 13 MRL/l mice with spontaneous lupus nephritis. Nine animals receiving no treatment were used as the control. FK506 significantly reduced the development of proteinuria, lowered the level of BUN, and suppressed the elevation of serum anti-dsDNA antibodies. Histopathological study showed that FK506 significantly inhibited the progression of glomerular hypercellularity and crescent formation. Glomerular deposition of C3 was significantly reduced in the FK506-treated mice compared to the nontreated controls. These findings suggest that FK506 may protect against progression of lupus nephritis in MRL/l mice, an animal model of systemic lupus erythematosus.

Total and regional bone mineral density by dual photon absorptiometry in patients on maintenance hemodialysis.

To evaluate bone loss in renal osteodystrophy, we measured total and regional (head, trunk, pelvis, leg and arm) bone mineral density (BMD) by dual photon absorptiometry in 72 patients on maintenance hemodialysis (HD). We also examined the validity of serum carboxy-terminal parathyroid hormone (C-PTH) and intact-PTH as an indicator of secondary hyperparathyroidism. Total BMD correlated inversely with age in female patients (r = -0.57, p less than 0.01), but not in male patients. Female patients older than 50 years were omitted from analysis to exclude the effect of menopause on bone. Among clinical and biochemical parameters, only trunk BMD correlated inversely with the duration of HD (r = -0.26, p less than 0.05). Head, trunk and total BMD correlated inversely with serum alkaline phosphatase, C-PTH and intact-PTH, while pelvis BMD did not. Leg and arm BMD also correlated inversely with serum intact-PTH, but not with serum C-PTH. The serum level of C-PTH correlated positively with the duration of HD (r = 0.40, p less than 0.005), while intact-PTH did not. As compared with 18 control male volunteers aged 25-42 years, trunk, pelvis, leg, arm and total BMD were significantly lower in male patients on HD aged 22-49 years, whereas head BMD did not differ significantly between the two groups. The percent decrease of BMD was most prominent in the trunk (-19.6%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the platelet-activating factor antagonists CV-6209 and CV-3988 on nephrotoxic serum nephritis in the rat.

Platelet-activating factor (PAF) is known as an important mediator in the pathogenesis of glomerular injury. In the present study, we evaluated the effect of the specific PAF antagonists CV-6209 and CV-3988 on accelerated nephrotoxic serum nephritis (NTN) in the rat. The amount of urinary protein excretion was significantly less in the rats treated with CV-6209 or CV-3988 on the 5th and 7th day of treatment than in the nontreated controls. The results of light- and immunofluorescence-microscopic examination did not demonstrate any favorable effect on glomerular changes by these PAF antagonists. However, CV-6209 protected against the loss of glomerular anionic charges in rats with NTN. Thus, it is suggested that PAF is a potent mediator of protein excretion, and that the loss of glomerular anionic charges is an important mechanism for the mediation of PAF in glomerulonephritis.