Abnormalities in glomerular function have been observed frequently in the early stages of both clinical and experimental diabetes mellitus. Because prostaglandins (PGs) are present in the glomerulus and have profound effects on glomerular hemodynamics, and because abnormalities of PG metabolism have been noted in other tissues from diabetics, we studied PG biosynthesis in glomeruli obtained from rats in the early stages of experimental diabetes mellitus. Streptozotocin, 60 mg/kg, was administered intravenously to male Sprague-Dawley rats. Control rats received an equal volume of the vehicle. Glomeruli were isolated 9-23 d later. Production of eicosanoids was determined by two methods: by direct radioimmunoassay after incubation of glomeruli under basal conditions and in the presence of arachidonic acid (C20:4), 30 pM, and by radiometric high-performance liquid chromatography (HPLC) after incubation of glomeruli with ['4C]C20:4. When assessed by radioimmunoassay, mean basal production of both prostaglandin E2 (PGE2) and prostaglandin F2. (PGF2.) was twofold greater in the diabetic animals whereas production of thromboxane B2 (TXB2) was not significantly greater than control. In response to C20:4, both PGE2 and PGF7, were also greater in the diabetic animals, but these differences were not statistically significant. The increased rate of basal PG production did not appear to be related directly to the severity of the diabetic state as reflected by the degree of hyperglycemia at the time of sacrifice. In fact, the rates of glomerular PG production in the individual diabetic animals correlated inversely with the plasma glucose concentration. The increased rate of PG synthesis did not appear to be due to a nonspecific effect of streptozotocin inasmuch as glomerular PG production was not increased significantly in streptozotocin-treated rats which were made euglycemic by insulin therapy. Furthermore, addition of streptozotocin, 1-10 mM, to the incubation media had no effect on PGE2 production by normal glomeruli. PGE2 production by normal glomeruli was also not influenced by varying the glucose concentration in the incubation media over a range of 1-40 mM. When metabolism of I'4C1C20:4 was evaluated by high-performance liquid chromatography conversion to labeled PGE2, PGFu,, TXB2, and hydroxyheptadecatrienoic acid by diabetic glomeruli was two-to threefold greater compared with that in control glomeruli, whereas no significant difference in conversion to 12-and 15-hydroxyeicosatetraenoic acid occurred. These findings indicate that glomerular cyclooxygenase but not lipoxygenase activity was increased in the diabetic animals. A concomitant increase in glomerular phospholipase activity may also have been present to account for the more pronounced differences in PG production noted in the absence of exogenous unlabeled C20:4. These abnormalities in PG biosynthesis by diabetic glomeruli may contribute to the altered glomerular hemodynamics in this pathophysiologic setting.
To investigate the phagocytic capability of glomerular mesangial cells and the biochemical events associated with phagocytosis, rat cultured mesangial cells were incubated in the presence of opsonized zymosan (STZ) and production of reactive-oxygen species and lipoxygenase products were determined. Mesangial cells were identified on the basis of morphologic (presence of microfilaments and pattern of staining by an anti-myosin antiserum) and physiologic (contractile activity in response to angiotensin II) characteristics. No contamination by esterase-positive cells was observed. Electron microscopy revealed that the phagocytic process started after 5 min of incubation, and affected approximately 50% of the cells. Superoxide anion (.O2-) and hydrogen peroxide (H2O2) generation by mesangial cells exposed to STZ increased with time and STZ concentration. Cells incubated with zymosan particles treated with heated serum produced undetectable amounts of .O2- and 6 times less H2O2 than cells exposed to STZ. Pretreatment by cytochalasin B produced a marked decrease in STZ-stimulated production of reactive oxygen species. [3H]Arachidonic acid was incorporated into mesangial cell phospholipids and its release and conversion into monohydroxyeicosatetraenoic acids (HETE) was measured by radiometric high performance liquid chromatography (HPLC). Incubation with STZ markedly stimulated the release of arachidonic acid from its phospholipid stores and its transformation into 11-, 12-, and 15-HETE. Lipoxygenase inhibitors inhibited STZ-stimulated H2O2 production, whereas they did not modify the phagocytic process as shown by the absence of any effect on the uptake of 125I-STZ by the mesangial cells. This study demonstrates that a high percentage of rat cultured mesangial cells phagocytose opsonized particles. The phagocytic process results in an oxidative burst that appears to be dependent on stimulation of the lipoxygenase pathway.
Vascular and glomerular diseases are frequent causes of acute or rapidly progressing renal failure in HIV-infected patients. Renal biopsy appears to be safe and useful for the diagnosis and the prognosis of the renal failure. High mortality rate is only observed in patients with ischaemic/toxic causes of acute renal failure.
In human and experimental glomerulonephritis, glomerular hypercellularity results both from accumulation of macrophages and proliferation of resident glomerular cells. The recent identification of macrophage-derived factors that stimulate mesangial and epithelial cell proliferation suggests that these factors might contribute to the hypercellularity. To determine the identity of such macrophage-derived growth factors, we studied the effect of leukotrienes (LTs)
The glomerular epithelial cells and the glomerular basement membrane are important constituents of the permselective barrier in the kidney. These are affected in diabetic nephropathy, one of the long-term complications in diabetic patients. Nonenzymatic glycosylation resulting in the accumulation of advanced glycosylation end products correlates with the development of longterm complications in diabetes. The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies show that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior and regulate cell behavior. In this paper we demonstrate that interactions of human glomerular epithelial cells with a nonenzymatically glycated matrix are altered with defective cell spreading, reduced phosphorylation of focal adhesion kinase and reduced activity of mitogen-activated protein kinase. These data suggest that matrix glycation interferes with normal cell-matrix interactions and intracellular signaling that can potentially result in differential gene expression contributing to the changes seen in diabetic nephropathy.
Hemolytic uremic syndrome (HUS) is an uncommon cause of end-stage renal failure in adults, and few data are available concerning the outcome of renal transplantation in these patients. We conducted this retrospective multicentric study to appreciate the outcome of adult renal transplant recipients whose primary disease was HUS. Sixteen patients, transplanted between 1975 and 1995, were included in the study. In each case, initial diagnosis of HUS was documented by a kidney biopsy. These 16 patients received a total of 25 allografts: 1 graft for 9 patients, 2 grafts for 5 patients, and 3 grafts for 2 patients. Nine patients (56%) developed definite clinical and pathologic evidence of recurrence on at least 1 graft. Four additional patients (25%) demonstrated only some clinical or pathologic evidence of recurrence which could not be distinguished from acute vascular rejection. Three patients had no sign of recurrence of the initial disease. The 1-year graft survival rate was 63% and the 5-year graft survival rate was 18.5%. In the group of patients with proven or possible recurrence (n = 13), the 1-year and 5-year graft survival rates were 49% and less than 10%, respectively. The recurrence was an early event, occurring before the end of the first month after transplantation in half the cases. The recurrence rate was 92% in non-nephrectomized patients and 50% in patients with bilateral nephrectomy. In the literature, 71 adult patients with primary HUS had received a total of 90 kidney grafts. Among them, 54% had a recurrence on their graft, which was diagnosed in 52% of the kidney transplants. It is note-worthy that when data from the literature are pooled with our results, the rate of recurrence appears to be significantly lower in binephrectomized patients than in patients with their native kidneys at the time of transplantation (5 of 14 versus 27 of 35 patients, respectively, p = 0.0155). By univariate analysis, no other risk factor for recurrence could be identified. Treatment with cyclosporine A did not influence the recurrence rate. We conclude that recurrence of HUS after renal transplantation is a frequent, early, and severe complication, leading rapidly to graft loss. Prospective studies are needed to confirm that bilateral nephrectomy prior to transplantation decreases the rate of recurrence.
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