Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A daily injection protocol with puromycin aminonucleoside (PAN) causes loss of sialic acid from the glomerular filter. These changes have been studied previously by colloidal iron staining, but we have recently shown that phosphotungstic acid (PTA) at low pH allows the demonstration of sialic acid groups in the glomerular basement membrane in ultrathin sections of glycolmethacrylate(GMA)-embedded rat kidney. With this technique the slit diaphragm is seen as a continuation of the luminal cell coat and the method also gives an idea of the sialic acid distribution at the podocyte plasma membrane. The availability of this method made it possible to reevaluate the results obtained earlier in aminonucleoside (PAN) nephrosis indicating a decrease in the sialic acid content of the glomerulus. Although there are changes in the epithelial architecture, the ultrastructural appearances of the basement membrane are only slightly altered in PAN nephrosis. Detachment of epithelial cells was variable in different animals. Seven days after the first injection of PAN, staining with PTA revealed local defects in the lamina rara externa which later became more extensive. In PAN-treated animals the luminal cell coat showed reduced staining and large areas of the plasma membrane were completely devoid of a cell coat. These changes coincided with the onset of heavy proteinuria. The results indicate that both the basement membrane and the epithelial plasma membrane are affected in PAN nephrosis, as revealed by decreased staining for sialic acid-containing molecules in the basement membrane and by changes in the epithelial cell coat. The defects in the cell coat material point to functional alterations at the level of the slit pores and it is suggested that the decrease in sialic acid content of the lamina rara externa may be partly responsible for defects in the size-selective filtration barrier in PAN nephrosis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Alterations in the sialic acid content of the rat glomerular filter in aminonucleoside nephrosis. 287 May 76

The present study provides a histochemical analysis of the macromolecular and cellular composition of focal and segmental glomerular hyalinosis and sclerosis (FSGHS) in the rat with special reference to the different types of lipids present and to the participation of monocytes. FSGHS was induced in male Wistar rats by unilateral nephrectomy (UN) or puromycin aminonucleoside (PAN) injections. Histochemical analysis of glomeruli with FSGHS in both models after 20 weeks of proteinuria revealed massive deposits of lipids. These lipid accumulations were shown to consist mainly of free and esterified cholesterol; triglycerides and phospholipids were present in small amounts. Monocytes, identified by the alpha-naphthyl acetate method for non-specific esterase activity were scanty in glomeruli affected by FSGHS with an average glomerular count of 0.1 in UN- and 0.2 in PAN-treated rats. When present, no preferential localization of monocytes in the lesions was observed. The progressive glomerular damage occurring once the process of hyalinosis and sclerosis has started may be related to the paucity of "scavenging" monocytes. Cholesterol may be one of the substances involved in the development of these glomerular changes.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Glomerular sclerotic lesions in the rat. Histochemical analysis of their macromolecular and cellular composition. 287 25

2-Bromo-(diglutathion-S-yl)hydroquinone [2-Br-(diGSyl)HQ] causes severe necrosis of the proximal renal tubules in the rat, elevations in blood urea nitrogen (BUN) and increased urinary excretion of protein, glucose, and lactate dehydrogenase. In contrast, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ caused differentially less toxicity than the diglutathionyl conjugate. None of these conjugates had any apparent effect on liver pathology and serum glutamate-pyruvate transaminase remained within the normal range. Pretreatment of rats with probenecid, an organic anion transport inhibitor, offered only slight protection against 2-Br-(diGSyl)HQ-mediated elevations in BUN, proteinuria, or glucosuria. In contrast, quinine, an organic cation transport inhibitor, potentiated the nephrotoxicity of 2-Br-(di-GSyl)HQ. Thus, in contrast to other nephrotoxic sulfur conjugates, probenecid-sensitive organic ion transport systems do not contribute to the kidney-specific toxicity of 2-Br-(diGSyl)HQ. However, inhibition of renal gamma-glutamyl transpeptidase by AT-125 completely protected rats from the nephrotoxic effects of 2-Br-(diGSyl)HQ. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, caused a 20-25% decrease in 2-Br-(diGSyl)HQ-mediated elevations in BUN and urinary excretion parameters. The isomeric 35S conjugates covalently bound to rat kidney 10,000 x g homogenate in the order 2-Br-6-(GSyl)HQ greater than 2-Br-5-(GSyl)HQ greater than 2-Br-3-(GSyl)HQ greater than 2-Br-(diGSyl)HQ. AT-125 (0.4 mM) decreased covalent binding by 25%, 17%, 33%, and 28%, respectively. Aminooxyacetic acid (0.1 mM) inhibited covalent binding by 26%, 10%, 17%, and 17% respectively. Ascorbic acid (1.0 mM) inhibited covalent binding by 63%, 87%, 62%, and 28%, respectively, and this inhibition correlated, inversely, with the redox potential of the conjugates. Thus, the covalent binding is mediated preferentially by oxidation of the quinol moiety, although the formation of reactive thiols cannot be excluded. In addition, the initial conjugation of 2-BrHQ with GSH does not result in the formation of a less redox-active species. However, the subsequent addition of a second molecule of GSH results in the formation of a more redox-stable compound, which, paradoxically, enhances toxicity. The metabolism of 2-Br-(diGSyl)HQ by renal proximal tubular gamma-glutamyl transpeptidase and trans-membrane transport of the cysteine conjugate(s) followed by oxidation of the quinol moiety is probably responsible for the target organ toxicity of this compound.
Mol Pharmacol 1988 Oct
PMID:2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: physiological, biochemical, and electrochemical determinants. 317 33

Renal histamine concentration, total histamine and protein contents were measured in rats made diabetic via iv streptozotocin injection and held for 13 weeks following diagnosis of diabetes. Insulin (7 U/day) or alpha-hydrazinohistidine (alpha-HH, 25 mg/kg/day) or both drugs were administered to diabetic subgroups the last 2 weeks of the holding period. Untreated diabetics developed significant increases of renal histamine concentration and total histamine content, up 45 and 46%, respectively. Drug interventions reduced the diabetic increases of histamine concentration and content (in order) as follows: diabetic-insulin, down 7 and 8%; diabetic-alpha-HH down 25 and 26%; diabetic-insulin + alpha-HH, down 35 and 36%. Renal tissue protein content was unchanged and qualitative proteinuria was present in all diabetic subgroups. The data indicate that in experimental diabetes there is an increase of the renal inducible histamine pool which is partially reduced by insulin and/or alpha-HH treatments. In view of the long-recognized actions of histamine upon microvascular permeability, elevated renal histamine may be one pathophysiological mediator of the diabetic functional renal microangiopathy manifest as proteinuria.
Exp Mol Pathol 1986 Feb
PMID:Renal histamine increases in the streptozotocin-diabetic rat. 351 88

Experiments were undertaken to clarify whether a large dose of methylprednisolone (MPSL) could have any suppressive effect on progressive Masugi nephritis in the rabbit. Progressive crescentic Masugi nephritis could be induced with high reproducibility by preimmunization with a small amount of nephrotoxic duck gamma-globulin incorporated with complete Freund's adjuvant, followed by an intravenous injection 4 days later. Two groups of rabbits treated with 80 mg/kg of MPSL either before or after the development of proteinuria, showed a significant decrease in both antibody titers and serum creatinine levels during treatment. Histologically, the prominent diffuse intracapillary proliferation and crescent formation observed in controls, were markedly diminished. Accumulations of monocytes in the intra- and extracapillary space were also decreased. These results suggest that suppression of antibody production by a large dose of MPSL is one of its most fundamental actions, and can prevent the processes leading to crescentic glomerular lesions.
Virchows Arch B Cell Pathol Incl Mol Pathol 1980
PMID:Effect of methylprednisolone on progressive Masugi nephritis in the rabbit. I. Suppression of antibody production and crescent formation. 611 Nov 56

Lowe's syndrome (oculo-cerebro-renal syndrome) has been studied biochemically. The disease was characterized by proteinuria, sialic aciduria and the excretion of undersulfated chondroitin sulfate A due mainly to malfunction of renal tubules. However, cultured skin fibroblasts from patients were found also to produce markedly undersulfated glycosaminoglycans. The undersulfation was caused by depressed sulfation rather than by increased desulfation. Subsequent studies have revealed that degradation of active sulfate (adenosine 3'-phosphate 5'-phosphosulfate, PAPS) was markedly elevated in the cells from patients whereas PAPS biosynthesis or sulfate transfer of sulfate from PAPS to glycosaminoglycan acceptors were normal. The enzyme involved in PAPS degradation was then identified as a nucleotide pyrophosphatase which is capable of degrading various nucleotides. The level of the enzyme activity in patients' cells was about ten times higher than that in normal cells and the level in heterozygotes were intermediate between patients and normal individuals. It was suggested that Lowe's syndrome is caused by elevation of biosynthesis of a nucleotide pyrophosphatase having a capacity to degrade PAPS due to a defect in regulating the enzyme synthesis.
Mol Cell Biochem 1983
PMID:Biochemical studies on Lowe's syndrome. 613 83

Experiments were undertaken to ascertain whether progression of crescentic Masugi nephritis in rabbits could be prevented by the administration of Bredinin (BR). Crescentic glomerulonephritis can be induced with high reproducibility by intramuscular preimmunization on day 1, followed by intravenous injections on days 3 and 5 of nephrotoxic duck gamma-globulin (NTD gamma-gl). 30 rabbits were divided into 3 groups including controls (group 1). Two groups of 10 nephritic rabbits were each treated with 10 mg/kg of BR either after or before the development of proteinuria (groups 2 and 3). In group 3, the onset of proteinuria showed a significant delay and duration of survival was significantly prolonged, compared with controls. Serum antibody titers after day 8 and creatinine levels after day 10, as well as the initial amounts of proteinuria, were also significantly lower during treatment in group 3 than in controls. Histologically, the prominent diffuse intra- and extra-capillary proliferation with monocyte accumulations observed in the control group were markedly diminished in group 3. These results suggest that early treatment in crescentic glomerulonephritis with BR will suppress the production of humoral antibody and prevent progression of the glomerular lesions.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:Modification of crescentic Masugi nephritis in the rabbit by Bredinin, a new immunosuppressant. 613 99

Using highly cationic polyethleneimine, alteration of glomerular anionic sites were evaluated ultrastructurally in two types of rat glomerulonephritis (GN); chronic serum sickness GN and heterologous (passive) or autologous (active) Heymann's GN. Daily i.v. injections of egg white lysozyme in physiologic saline into presensitized rats led to the formation of numerous mesangial and subepithelial deposits. In the non-proteinuric period in which immune deposits were localized predominantly in the mesangium, anionic sites of the laminae rarae and the epithelial cell coat were clearly observed. In the subsequent proteinuric period in which numerous subepithelial deposits were superimposed, a broad loss of anionic sites in the epithelial cell coat was seen. Splitting and focal loss of anionic sites on the lamina rara externa adjacent to the subepithelial deposits were commonly observed both in passive and active Heymann's GN and in lysozyme GN. These findings indicate that the subepithelial deposits are closely involved in the development of proteinuria by injuring the anionic sites, especially those on lamina rare externa of the glomerular basement membrane.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:Alteration of glomerular anionic sites by the development of subepithelial deposits in experimental glomerulonephritis in the rat. 613 11

The autoimmune manifestations of MRL-+/+ (MRL/n) and MRL/Mp-lpr/lpr (MRL/l) murine models of systemic lupus erythematosus (SLE) were successfully reversed following total lymphoid irradiation (TLI) therapy consisting of 8-12 daily fractions of 200 rad. Following radiotherapy the characteristic lymphadenopathy of MRL/l disappeared, proteinuria was 334 mg% compared to a peak of 2272 mg% in untreated controls, and the median survival time was prolonged to 423 days compared to 214 days in untreated mice. The albuminuria of TLI-treated MRL/n mice was 194 mg% compared to 1180 mg% in untreated controls. The survival of treated MRL/n mice was prolonged to a median of 389 as compared to 190 days in untreated controls. The effect of TLI on antiDNA antibodies in both MRL/l and MRL/n was less remarkable. However, the antiDNA activity reached normal levels in most long-living mice. The most impressive finding was complete reversal and/or prevention of the SLE-like glomerulonephritis in MRL/l mice as documented by light and electron microscopy. Immunomanipulation with TLI should be further evaluated as a possible treatment modality in intractable human autoimmune disorders.
Exp Mol Pathol 1983 Feb
PMID:Successful treatment of autoimmune manifestations in MRL/l and MRL/n mice using total lymphoid irradiation (TLI). 633 70

Studies were conducted to assess the renal functional state in two recently discovered diabetic chimpanzees. Both were nonobese, adult female animals with the non-insulin-dependent form of impaired glucose tolerance, analogous to the Type II or nonobese, maturity-onset diabetes of humans. Both animals displayed moderate-to-heavy proteinuria and glycosuria in response to intravenous administration of glucose or tolbutamide. Chimpanzee number 333, but not number 1037, had fasting proteinuria and chronic hypertension. Renal function studies, using the inulin clearance method, demonstrated significantly decreased glomerular filtration rates and elevated rates of sodium excretion for both animals. The rate of chloride excretion was also elevated in animal number 1037, but potassium excretion was apparently unaffected in both animals. Abnormal serum biochemical parameters demonstrated for chimpanzee number 333 included elevations in calcium, magnesium, creatinine, urea nitrogen, and uric acid; animal number 1037 had only an elevated serum creatinine. Results are consistent with the occurrence of renal disease similar to the nephropathy that develops in human diabetics. The difference in severity of renal impairment in the two chimpanzees is possibly related to differences in duration and severity of impaired glucose tolerance. A progression of both diabetic and renal disorders is most probable.
Exp Mol Pathol 1983 Apr
PMID:Impaired renal function in diabetic chimpanzees (Pan troglodytes). 683 45


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