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J Scholey

Publications and source records attributed to J Scholey.

11 recordsLinked to original sources
PubMed2000

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Increased flux through the hexosamine biosynthetic pathway is associated with altered gene expression. To investigate the underlying mechanisms, we treated glomerular mesangial cells with glucosamine and studied the regulation of the plasminogen activator inhibitor (PAI)-1 gene. Incubating mesangial cells with 2 mmol/l glucosamine for 4 days resulted in a 3.1+/-0.4-fold increase in PAI-1 mRNA levels (P < 0.01) and a 33+/-9-fold increase in the activity of a transiently transfected PAI-1 promoter-luciferase reporter gene (P < 0.01). Cotransfection of an expression vector for a dominant-negative type II TGF-beta receptor with the PAI-1 promoter-reporter gene did not interfere with this effect of glucosamine. However, mutation of 2 putative Sp1 sites in the PAI-1 promoter, at -76 to -71 and -44 to -39, markedly reduced induction of PAI-1 luciferase activity by glucosamine, from 8.9+/-1.9-fold to 1.7+/-0.5-fold (P < 0.01). An electrophoretic mobility shift assay demonstrated that glucosamine increased Sp1 DNA binding by 31+/-11% (P < 0.05), implying that the effects of glucosamine were explained, in part, by changes in Sp1 DNA binding. High glucose (20 mmol/l) also activated the transiently transfected PAI-1 promoter (2.5+/-0.4-fold). This effect was diminished by mutation of both the PAI-1 promoter Sp1 sites (1.2+/-0.3-fold, P < 0.05). In addition, 6-diazo-5-oxo-L-norleucine, a glutamine:fructose-6-phosphate-amidotransferase inhibitor, blocked the induction by high glucose (4.7+/-0.8- to 0.9+/-0.1-fold, P < 0.01). These results indicate that stimulation of the PAI-1 promoter by both high glucose and glucosamine involves Sp1 and that the hexosamine pathway may be involved in the regulation of gene expression by high glucose in glomerular mesangial cells.

Animals↗
PubMed1997

Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients.

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.

Adult↗
PubMed1996

Glomerular dysfunction in the aging Fischer 344 rat is associated with excessive growth and normal mesangial cell function.

BACKGROUND: Fischer 344 (F344) rats display focal and diffuse glomerulosclerosis with aging postulated to result from loss of normal mesangial cell intrinsic function, e.g., vasoactive hormone signaling, or preservation of normal responsiveness to extrinsic growth factors. METHODS: In 3-, 17-, and 24-month-old F344 male rats, glomerular structure, measured by PC-based morphometry, and function were compared. Immunoperoxidase staining of glomerular proliferating cell nuclear antigen (PCNA) detected cellular proliferation. Primary cultured mesangial cells from the 3 age groups were studied in parallel. Calcium (Ca2+) signaling, measured by Fura-2 fluorescence, contraction to vasopressin (AVP) 1 microM, measured by videomicroscopy, and proliferative response to platelet-derived growth factor-beta beta (PDGF) were compared. RESULTS: Proteinuria was 13 +/- 4, 38 +/- 17, and 110 +/- 35 mg/24 hours at 3, 17, and 24 months, respectively (n = 5, mean +/- SE, p < .01, 3 vs 24 months), with no change in 24-hour creatinine clearances. Glomerular volumes (n = 200/group) for 3, 17, and 24 months, respectively, were .30 +/- .01, .60 +/- .02, .74 +/- 0.2 x 10(6) micron3 (p < .001, 3 months vs 17 months, and 17 vs 24 months). Glomerular basement membrane (GBM) widths and fractional mesangial volumes increased significantly with aging. Glomerular cell PCNA staining remained positive at 24 months. Cultured mesangial cell Ca2+ signaling and contraction to AVP were unchanged with aging. Proliferation to PDGF, which was partially inhibited with verapamil, was similar at 3 and 24 months. CONCLUSIONS: In the Fischer 344 rat, mesangial cell Ca2+ signaling, contraction, and proliferation responsiveness are unchanged with aging. Continued growth is associated with the glomerulosclerosis of aging.

Aging↗
PubMed1995

Identification of the chromosome localization domain of the Drosophila nod kinesin-like protein.

The nod kinesin-like protein is localized along the arms of meiotic chromosomes and is required to maintain the position of achiasmate chromosomes on the developing meiotic spindle. Here we show that the localization of ectopically expressed nod protein on mitotic chromosomes precisely parallels that observed for wild-type nod protein on meiotic chromosomes. Moreover, the carboxyl-terminal half of the nod protein also binds to chromosomes when overexpressed in mitotic cells, whereas the overexpressed amino-terminal motor domain binds only to microtubules. Chromosome localization of the carboxyl-terminal domain of nod depends upon an 82-amino acid region comprised of three copies of a sequence homologous to the DNA-binding domain of HMG 14/17 proteins. These data map the two primary functional domains of the nod protein in vivo and provide a molecular explanation for the directing of the nod protein to a specific subcellular component, the chromosome.

Animals↗
PubMed1994

Interaction of dietary fatty acids and cyclosporine A in the borderline hypertensive rat: tissue fatty acids.

In this study we examined (i) the effects of cyclosporine A (CS) on tissue lipid composition and (ii) the effect of changes in dietary n-6 fatty acids on tissue responses to CS. Fatty acid composition of liver, kidney, heart and brain were determined after 4 wk of treatment with CS (10 mg/kg.d p.o.) in male borderline hypertensive rats (BHR, n = 4/group), whose diet was supplemented with either safflower oil or evening primrose oil (EPO). Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine/phosphatidylinositol, triglyceride and cholesteryl ester fatty acids were measured in kidney, heart, brain and liver. The same parameters were also measured in safflower-fed BHR (n = 4) receiving placebo. The effects of CS on liver microsomal delta 9, delta 6 and delta 5 desaturases in vitro were also followed. CS affected the fatty acid composition of all tissues examined, with the greatest changes seen in the renal phosphatidylcholine and phosphatidylserine/phosphatidylinositol fractions. All CS-induced changes that occurred in the liver, brain and renal fatty acids were reversed by EPO. CS elevated delta 9 desaturase but had no effect on delta 6 and delta 5 desaturase. In light of (i) the observation that EPO normalizes renal function and blood pressure in CS-treated BHR, and (ii) the importance of the kidney in blood pressure regulation, the data suggest that the beneficial effects of EPO on CS toxicity may involve changes in renal phospholipid fatty acid profiles.

Animals↗
PubMed1992

Attenuation of cyclosporine-induced hypertension by dietary fatty acids in the borderline hypertensive rat.

The effects of dietary (10% calories) safflower (SAF), evening primrose (EPO), and fish oil (F) as sources of linoleic acid (control), gamma-linolenic acid, and long-chain n-3 fatty acids, respectively, on cardiovascular and renal responses to chronic (5 weeks) cyclosporine administration were studied in male borderline hypertensive rats. In one experiment (n = 9/group), oral administration of CsA at 0.1 mg/kg.day significantly increased awake systolic blood pressure vs. placebo in SAF-fed rats (P less than 0.01). This increase was prevented by both EPO (P less than 0.001) and F (P less than 0.01), in the absence of group differences in body weight gain or plasma electrolyte levels. In a second experiment, CsA also increased blood pressure vs. placebo in SAF-fed rats (P less than 0.001). While this increase was prevented by EPO (P less than 0.001), F had no significant effect. Differences in group blood pressure responses were not explained by group differences in body weight gain or trough levels of blood CsA. Renal function, assessed in anesthetized rats after week 5, demonstrated a CsA-related (10 mg/kg.day) decrease in whole-kidney GFR in SAF-fed animals vs. placebo (P less than 0.05) that was prevented by EPO and attenuated by F. EPO and F also tended to reduce the CsA-induced elevation in renovascular resistance, but this difference did not reach statistical significance. These findings suggest the potential of dietary EPO and F to offset nephrotoxic effects of CsA administration, and suggest that EPO may also be useful in countering CsA-induced hypertension.

Animals↗
PubMed1986

Celiac sprue-associated immune complex glomerulonephritis.

A 35-year-old man developed leg edema, marked hypoalbuminemia, and proteinuria. Subsequent renal biopsy revealed a diffuse membranoproliferative glomerulonephritis and, on electron microscopy, typical electron-dense deposits characteristic of an immune complex pathogenesis. Although protein wasting might have readily been explained on the basis of his nephrotic syndrome, the concomitant symptom of diarrhea led to the diagnosis of celiac sprue, another disorder with a possible immune-mediated pathogenesis. While reports of immune complex glomerulonephritis in celiac sprue are rarely recorded, the potential significance of gastrointestinal symptoms in patients with the nephrotic syndrome may have important nutritional implications, especially if underlying occult celiac sprue is recognized.

Adult↗