CJASN
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published ahead of print on December 28, 2005
Clin J Am Soc Nephrol 1: 263-268, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00990905
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
CJN.00990905v1
1/2/263    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McGowan, T. A.
Right arrow Articles by Sharma, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McGowan, T. A.
Right arrow Articles by Sharma, K.

Diabetes and the Kidney

Stimulation of Urinary TGF-ß and Isoprostanes in Response to Hyperglycemia in Humans

Tracy A. McGowan*, Stephen R. Dunn{dagger}, Bonita Falkner{ddagger}, and Kumar Sharma*,{dagger}

* Center for Diabetic Kidney Disease, {dagger} Cell and Molecular Biology of Kidney Disease-Dorrance Hamilton Research Laboratories, and {ddagger} Center for Hypertension, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence to: Dr. Kumar Sharma, Thomas Jefferson University, Department of Medicine, 353 Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107. Phone: 215-503-6950; Fax: 215-923-7212; E-mail: kumar.sharma{at}jefferson.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
TGF-ß and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-ß1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-ß1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-ß1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-ß1 in plasma was 4.57 ± 0.22 ng/ml, and no change in plasma TGF-ß1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-ß1 was 4.14 ± 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-ß1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-ß1 of 30.43 ± 8.05 pg/mg (P = 0.002). TGF-ß1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 ± 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 ± 0.74 to 13.8 ± 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-ß1 and isoprostane production.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Pathologic characteristics of diabetic nephropathy include early increases in glomerular and tubular compartments followed by progressive thickening of glomerular basement membranes and mesangial matrix accumulation. Clinically, these changes are associated with augmented glomerular blood flow in the early stages and enhanced glomerular permeability to albumin with a decline in GFR in the later stages (1). The mechanisms that initiate and mediate the renal pathology in patients with diabetes are not fully resolved but seem to involve regulatory alterations within the tissue. In vitro studies have shown that exposure of renal cells to high ambient glucose stimulates hypertrophy and production of collagen types I and IV in proximal tubular and mesangial cells (2–4). On the basis of experimental studies, the accumulation of excess matrix, through both increased production and decreased degradation, seems to advance the diabetic renal pathology (5). Two of the pathways that may mediate the renal complications of diabetes include TGF-ß and reactive oxygen species (ROS) generation (6).

TGF-ß has been found to stimulate extracellular matrix proteins including fibronectin, type IV and type I collagen. TGF-ß also impairs proteolytic degradation of collagen fibers through a decrease in synthesis and secretion of matrix metalloproteinases and an increase in synthesis of tissue inhibitors of metalloproteinases (7). In vitro studies have detected an increase in TGF-ß1 mRNA expression and bioactivity in mesangial and tubular cells when exposed to high glucose concentration (8). Renal TGF-ß1 mRNA levels are also increased in diabetic mice and rats within 48 h after onset of hyperglycemia. Recent studies that evaluated glucose-induced TGF-ß1 production demonstrated a key role for the upstream stimulatory factor family of transcription factors in vitro as well as in vivo (9,10). The causative role of TGF-ß in stimulating early gene expression of matrix molecules as well as mesangial matrix accumulation is supported by experiments with neutralizing antibodies in streptozotocin-induced diabetic mice and in db/db mice (11,12). In patients with diabetes, there is increased renal production of TGF-ß in both early and advanced disease (13,14). However, it remains unclear whether transient hyperglycemia itself is sufficient to stimulate renal TGF-ß production in humans.

Increased oxidant stress has also been recognized to play a key role in mediating glucotoxicity in a variety of animal models of diabetic complications (15,16). Recent laboratory investigations have identified a link between oxidized free radicals and upregulation of TGF-ß activity (17,18). In the streptozotocin-induced diabetic rat model, Montero et al. (19) found a marked increase in plasma levels and urinary excretion of F2-isoprostane. In tissue culture, a high ambient glucose increased F2-isoprostane synthesis in glomerular endothelial and mesangial cells. Incubation of glomerular cells with F2-isoprostanes stimulated the production of TGF-ß (18). It is interesting that TGF-ß has also been recognized to stimulate ROS production in renal and vascular cells, suggesting that there may be a positive feedback pathway between TGF-ß and ROS (20).

In patients with established diabetes, there are numerous acute and chronic metabolic derangements as well as hemodynamic stresses that all may contribute to increased production of renal TGF-ß and increase oxidant stress. These factors include hyperglycemia, hexosamines, glycated proteins, protein kinase C activation, and increased glomerular pressure. Although many pathways are stimulated within hours of exposure to hyperglycemia, some pathways require weeks to months to occur, e.g., glycation of proteins. Therefore, it is difficult to identify the key components that may provide the dominant stimulus for renal TGF-ß production in humans with diabetes. In an attempt to limit the number of variables involved, we performed a study to raise glycemia levels in normal volunteers and measured levels of TGF-ß and isoprostanes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Human Protocol
Healthy volunteers were enrolled in this study after written informed consent was obtained on a Thomas Jefferson University approved Institutional Review Board protocol. Each volunteer was instructed to obtain a timed overnight urine sample and report to the Renal Clinical Research Unit at 8 a.m. after a 12-h overnight fast. The overnight urine sample served as the baseline sample for urine TGF-ß and F2-isoprostanes. Venous catheters were placed in each arm, one for infusion and one for obtaining blood samples. A fasting blood sample was obtained for measurement of baseline plasma glucose and TGF-ß1. An infusion of 20% glucose was delivered in bolus to raise the plasma glucose to 200 mg/dl. Plasma glucose was measured every 5 min, and the glucose infusion rate then was adjusted to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. The plasma glucose then was tapered to 120 mg/dl by reduction in the glucose infusion rate over the next 30 min. Urine samples were collected at the end of the infusion and on each void thereafter during the day of the infusion. Another timed overnight urine sample was collected the next morning. The urine samples were assayed for urine creatinine and TGF-ß1. Plasma samples were collected before the start of the infusion and at 60-min intervals throughout the hyperglycemic infusion and assayed for TGF-ß1 and insulin. To determine whether there was evidence of oxidative stress from the steady-state hyperglycemia, F2-isoprostanes were also measured in the urine samples. Glucose was analyzed by the glucose oxidase technique with the Glucostat analyzer (Model 27; YSI Inc, Yellow Springs, OH). Creatinine concentration in urine and plasma samples was assayed using a NOVA analyzer.

TGF-ß1 Measurements
TGF-ß1 in urine was assayed by a method previously described and developed by Sharma and Dunn (www.jeffersonhospital.org/cdkd) (21). This assay uses a sandwich ELISA (Quantikine kit for Human TGF-ß1 Immunoassay; R&D Systems, Minneapolis, MN). Urine samples were initially concentrated and pH was adjusted to activate latent TGF-ß to active TGF-ß. Corrections were made for urine concentration by measuring urinary creatinine, and values were expressed as TGF-ß1 in pg/g creatinine. The correlation coefficient with standards is >0.98, and the lowest detectable limit for measurement is 0.7 pg/ml. The reliability of this assay for urinary TGF-ß1 is high with an intra-assay coefficient of variation of 2.5 ± 3.0% and an interassay coefficient of variation of 5.6 ± 4.2%. Recovery of fortified TGF-ß1 added to urine samples was 94%. No interference from TGF-ß2 was observed. Plasma levels of TGF-ß1 were measured using the method of Wakefield et al. (22).

Measurement of Urinary F2-Isoprostanes
Isoprostanes are prostaglandin-like compounds that are produced by free radical–mediated peroxidation of lipoproteins. Urinary levels of 15-isoprostane F2t (also known as 8-epi-PGF2{alpha} or 8-iso-PGF2{alpha}) has been used for the noninvasive assessment of oxidative stress in patients with diabetes and experimental models of diabetes (19,23). It has been shown that unmetabolized cyclo-oxygenase-–derived prostaglandins in urine derive almost exclusively from their local formation in the kidney. In this study, we measured urinary levels of 15-isoprostane F2t using a competitive ELISA (Oxford Biomedical Research, Oxford, MI). In this assay, urine samples are mixed with an enhancing reagent that essentially eliminates interferences as a result of nonspecific binding. The 15-isoprostane F2t in the samples competes with 15-isoprostane F2t conjugated to horseradish peroxidase for binding to a polyclonal antibody specific for 15-isoprostane F2t coated on the microplate. The horseradish peroxidase activity results in color development when substrate is added, with the intensity of the color proportional to the amount of 15-isoprostane F2t bound and inversely proportional to the amount of unconjugated 15-isoprostane F2t in the samples. A Spectramax 250 plate reader (Molecular Devices, Sunnyvale, CA) was used to measure the absorbance at 450 nm. Samples were run with known standards. Urinary samples were also run in duplicate, and the average of these values was used to determine the corresponding 15-isoprostane F2t concentration from the standard curve. The manufacturer’s reported correlation of this immunoassay when compared with gas chromatography/mass spectrometry of the same human urine samples is >0.8. Use of this assay in our laboratory indicates reliable results with a low coefficient of variation (<5%).

Statistical Analyses
Unless otherwise stated, arithmetic means and SEM are reported. A paired t test was used to compare baseline levels with peak levels during and after the glycemic clamp. For comparison of three variables (baseline, after glucose clamp, and after overnight), a single-factor ANOVA with repeated measure was used. P < 0.05 for a two-sided test was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Complete data were obtained on 13 volunteers. The clinical characteristics are reported in Table 1. The sample included six men and seven women with a mean age of 39 yr. The ethnic distribution of the sample was 10 white, two Asian, and one Hispanic. All volunteers had BP in the normal range and no evidence of renal dysfunction.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics of study population

 
Before the hyperglycemic clamp, all patients had levels of fasting blood glucose in the normal range (Table 2). During the hyperglycemic clamp, the blood glucose ranged between 200 and 280 mg/dl beginning at approximately 15 min after the beginning of glucose infusion and lasting for 120 min. There was an expected rise in plasma insulin levels during the hyperglycemic clamp. The mean baseline TGF-ß1 level in plasma was 4.57 ± 0.22 ng/ml. No change in plasma TGF-ß levels was detected during the hyperglycemia period (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Plasma levels of glucose, insulin, and TGF-ß1 at baseline and during hyperglycemic clamp

 
The mean baseline urine TGF-ß1 level (corrected for creatinine excretion) was 4.14 ± 1.16 pg/mg creatinine. Figure 1 depicts the urinary TGF-ß1 excretion before and after the 2-h period of steady-state stable hyperglycemia. The fractional urine samples showed a sharp increase (seven-fold) in TGF-ß1 excretion (30.3 ± 8.05 pg/mg; P = 0.002) within the 12-h period after exposure to hyperglycemia. The time from the beginning of the glucose infusion to a mean peak TGF-ß excretion was 7.44 ± 1.36 h. TGF-ß excretion in the subsequent overnight urine sample after the hyperglycemic clamp was not significantly different from baseline (4.6 ± 1.21 pg/mg; P = 0.760).


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. Urinary TGF-ß1 before and after hyperglycemic clamp. The baseline urine TGF-ß1 level was 4.14 ± 1.16 pg/mg creatinine. After the hyperglycemic clamp, the mean peak level rose to 30.43 ± 8.05 pg/mg creatinine (P = 0.0002). On the overnight fasting urine measurement the following day, the urine TGF-ß1 level decreased back to the baseline value of 4.62 ± 1.21 pg/mg creatinine.

 
To determine whether evidence of oxidative stress could be detected in response to hyperglycemia, we assayed F2-isoprostane on the urine samples that were collected before and after the glucose infusion. The results of the assays on F2-isoprostane excretion are depicted in Figure 2. The mean baseline F2-isoprostane excretion, on the overnight samples before glucose infusion, was 4.92 ± 0.74 ng/mg creatinine. After the glucose infusion, F2-isoprostane excretion increased to 13.81 ± 3.37 ng/mg creatinine (P = 0.001). The mean level reverted back to baseline in the next overnight sample (5.06 ± 0.67 ng/mg creatinine; P = 0.882).


Figure 2
View larger version (9K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. Urinary isoprostanes before and after hyperglycemic clamp. The mean baseline F2 isoprostane excretion, on the overnight samples before glucose infusion, was 4.92 ± 0.74 ng/mg creatinine. After the glucose infusion, isoprostane excretion increased to 13.81 ± 3.37 ng/mg creatinine (P = 0.001). On the overnight fasting urine measurement the following day, the value was similar to baseline at 5.06 ± 0.67 ng/mg creatinine.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
These data indicate that exposure to hyperglycemia in the range of 200 to 250 mg/dl for a period of 2 h is sufficient to upregulate urinary TGF-ß1 and isoprostane excretion in healthy nondiabetic volunteers. It is of note that this level of hyperglycemia approximates the glycemic load observed in suboptimal control of patients with diabetes. In addition, patients with established diabetes will often have transient levels of hyperglycemia that exceed 200 mg/dl. The upregulation of TGF-ß1 identified in the urine could not be detected in the plasma, suggesting that TGF-ß1 is produced primarily in renal tissue.

Our data are supportive of previous studies that showed elevations in urinary levels of TGF-ß in patients who have diabetes without a corresponding elevation in systemic levels of TGF-ß1 (13,24). Urinary levels of TGF-ß are considered to be a valid measure of renal production of TGF-ß1, as in our previous study we found that net renal production of TGF-ß1 was associated with increased urine levels (13).

Our data demonstrate that hyperglycemia by itself is a potent stimulus for renal TGF-ß and is likely relevant to the human diabetic condition. The relatively modest levels of hyperglycemia induced in this study are commonly seen in patients with diabetes, especially after exposure to glycemic loads. The short duration of hyperglycemia is insufficient for advanced glycation of proteins by either Amadori modification or advanced glycation; thus, our study also determines that short-term hyperglycemia-induced stimulation of renal TGF-ß1 production likely is not dependent on glycated proteins. Other pathways that are considered to mediate glucotoxicity, such as the hexosamine pathway, protein kinase C activation, extracellular signal–regulated kinase activation, and hemodynamic stress, may be involved in mediating this acute effect of hyperglycemia on renal TGF-ß production (25,26). However, several cell culture studies suggest that activation of these pathways requires 24 h or more of sustained high glucose (27,28). An effect of modest hyperglycemia on the renin-angiotensin system is another potential pathway that may mediate upregulation of renal TGF-ß production (29,30). It is likely that more than one pathway may be activated within hours of transient hyperglycemia as numerous hemodynamic and cellular systems are activated by glucose stress. Data from this study indicate that even short-term hyperglycemia (120 min) is sufficient to mediate glucotoxic pathways that culminate in production of TGF-ß1 in the human kidney. Of note, the marked increase in urinary levels of TGF-ß1 protein occurred much quicker and with greater magnitude than has been found in studies with cell culture (31). It is likely that multiple pathways are stimulated by transient glucose elevations in vivo and are unable to be mimicked adequately in a cell culture system.

There was no observed increase in plasma TGF-ß1 levels during the 120 min of hyperglycemia. It is possible that there could have been a delayed response in the postinfusion period that coincided with the urine peak. A limitation of this study was that plasma TGF-ß1 levels after hyperglycemia were not available.

A role for insulin to raise TGF-ß1 is possible as insulin levels rise dramatically with the glycemic infusion. However, we have not found evidence of increased urine levels of TGF-ß in a separate study wherein patients underwent euglycemic hyperinsulinemic clamps (unpublished data). A role for osmotic stress may have contributed to the increase in urinary TGF-ß1. Although cell culture studies with osmotic controls for d-glucose do not elicit TGF-ß1 production (31), an osmotic control was not included and remains a limitation of our study.

It was demonstrated that high glucose stimulates free radicals (32,33), and this may be the link between hyperglycemia and the subsequent glucotoxic pathways that lead to complications of diabetes (34). In fact, studies by Brownlee and colleagues (17,33) have found that high glucose stimulation of TGF-ß1 and cyclo-oxygenase 2 in cell culture may be mediated by ROS generation via the mitochondria. Our studies are supportive of this concept as urinary F2-isoprostane levels increased after short-term hyperglycemia, which would be consistent with ROS generation in the kidney. Whether ROS generation is upstream and/or downstream of renal TGF-ß production remains to be determined. The source of oxidant stress with transient hyperglycemia is unclear but likely reflects renal and possibly systemic oxidant production.

Recent studies have suggested that the prediabetic condition of impaired glucose tolerance is associated with an increase in cardiovascular events as well as kidney disease (35,36). Our data are supportive of the concept that even modest levels of hyperglycemia are sufficient to impose glucotoxic effects on renal cells as evidenced by urinary F2-isoprostane and TGF-ß1 levels. This is an important finding in light of the data presented by Ceriello et al. (37) that individuals with diabetes have an increased level of free radical generation after a standard meal compared with individuals without diabetes. Coutinho et al. (38) also reported that there is a positive correlation between glucose levels and cardiovascular risk that extends even below the diabetic threshold.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We have found that short-term modest hyperglycemia is a potent stimulus of renal TGF-ß1 production and oxidative stress generation in normal humans. The further study of these two mediators in relation to candidate stimuli in patients with diabetes will lead to a better understanding of the complex relationships between glucose homeostasis, TGF-ß1, and the oxidative stress pathways. A better understanding of these relationships will hopefully lead to targeted therapeutic paradigms to alter disease course.


   Acknowledgments
 
The studies were partially funded by grants to B.F. (NIH DK046107 and HL51547) and K.S. (NIH DK63017).

Portions of this article were presented in abstract form at the American Society of Nephrology Meeting; San Francisco, CA, October 10 to 17, 2001.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received September 8, 2005. Accepted November 7, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. McGowan T, McCue P, Sharma K: Diabetic nephropathy. Clin Lab Med 21: 111–146, 2001[Medline]
  2. Wolf G, Neilson EG, Goldfarb S, Ziyadeh FN: The influence of glucose concentration on angiotensin II-induced hypertrophy of proximal tubular cells in culture. Biochem Biophys Res Commun 176: 902–909, 1991[CrossRef][Medline]
  3. Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, Haverty TP: High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule. Am J Physiol 259: F704–F714, 1990[Medline]
  4. Ziyadeh FN, Sharma K, Ericksen M, Wolf G: Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by activation of transforming growth factor-b. J Clin Invest 93: 536–542, 1994[Medline]
  5. Ziyadeh FN: The extracellular matrix in diabetic nephropathy. Am J Kidney Dis 22: 736–744, 1993[Medline]
  6. Ziyadeh FN, Sharma K: Overview: Combating diabetic nephropathy. J Am Soc Nephrol 14: 1355–1357, 2003[Free Full Text]
  7. Sharma K, Ziyadeh FN: The emerging role of transforming growth factor-beta in kidney diseases. Am J Physiol 266: F829–F842, 1994[Medline]
  8. Sharma K, Ziyadeh FN: Hyperglycemia and diabetic kidney disease: The case for transforming growth factor-b as a key mediator. Diabetes 44: 1139–1146, 1995[Abstract]
  9. Zhu Y, Casado M, Vaulont S, Sharma K: Role of upstream stimulatory factors in regulation of renal transforming growth factor-beta1. Diabetes 54: 1976–1984, 2005[Abstract/Free Full Text]
  10. Weigert C, Brodbeck K, Sawadogo M, Haring HU, Schleicher ED: Upstream stimulatory factor (USF) proteins induce human TGF-beta1 gene activation via the glucose-response element-1013/-1002 in mesangial cells: Up-regulation of USF activity by the hexosamine biosynthetic pathway. J Biol Chem 279: 15908–15915, 2004[Abstract/Free Full Text]
  11. Sharma K, Guo J, Jin Y, Ziyadeh FN: Neutralization of TGF-b by anti-TGF-b antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45: 522–530, 1996[Abstract]
  12. Ziyadeh F, Hoffman B, Han D, Iglesias-de la Cruz C, Hong S, Isono M, Chen S, McGowan T, Sharma K: Long-term prevention of renal insufficiency excess matrix gene expression and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-b antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 97: 8015–8020, 2000[Abstract/Free Full Text]
  13. Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kurnik BRC, Kurnik PB, Weisberg LS: Increased renal production of transforming growth factor-beta1 in patients with type II diabetes. Diabetes 46: 854–859, 1997[Abstract]
  14. Yamamoto T, Nakamura T, Noble NA, Ruoslahti, E, Border WA: Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A 90: 1814–1818, 1993[Abstract/Free Full Text]
  15. Frisbee J, Maier K, Stepp D: Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats. Am J Physiol Heart Circ Physiol 283: H2160–H2168, 2002[Abstract/Free Full Text]
  16. Koya D, Hayashi K, Kitada M, Kashiwagi A, Kikkawa R, Haneda M: Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol 14[Suppl]: S250–S253, 2003[Abstract/Free Full Text]
  17. Du X, Edelstein D, Rosetti L, Fantus I, Goldberg H, Ziyadeh F, Wu J, Brownlee M: Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97: 12222–12226, 2000[Abstract/Free Full Text]
  18. Iglesias-De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, Rodriguez-Puyol M, Ziyadeh FN, Rodriguez-Puyol D: Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int 59: 87–95, 2001[CrossRef][Medline]
  19. Montero A, Munger K, Khan R, Valdivielso J, Morrow J, Guasch A, Ziyadeh F, Badr K: F(2)-isoprostanes mediate high glucose-induced TGF-beta synthesis and glomerular proteinuria in experimental type I diabetes. Kidney Int 58: 1963–1972, 2000[CrossRef][Medline]
  20. Sharma K, Cook A, Smith M, Valancius C, Inscho E: TGF-beta impairs renal autoregulation via generation of ROS. Am J Physiol Renal Physiol 288: F1069–F1077, 2005[Abstract/Free Full Text]
  21. Agarwal R, Siva S, Dunn SR, Sharma K: Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels. Am J Kidney Dis 39: 486–492, 2002[Medline]
  22. Wakefield L, Letterio J, Chen T, Danielpour D, Allison R, Pai L, Denicoff A, Noone M, Cowan K, O’Shaughnessy J, et al.: Transforming growth factor-beta1 circulates in normal human plasma and is unchanged in advanced metastatic breast cancer. Clin Cancer Res I: 129–136, 1995
  23. Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C: In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: Effects of improved metabolic control and vitamin E supplementation. Circulation 99: 224–229, 1999[Abstract/Free Full Text]
  24. Ellis D, Forrest K, Erbey J, Orchard TJ: Urinary measurement of transforming growth factor-beta and type IV collagen as new markers of renal injury: Application in diabetic nephropathy. Clin Chem 44: 950–956, 1998[Abstract/Free Full Text]
  25. Sharma K, McGowan T: TGF-beta in diabetic kidney disease: Role of novel signalling pathways. Cytokine Growth Factor Rev 11: 115–123, 2000[CrossRef][Medline]
  26. Hoffman BB, Sharma K, Ziyadeh FN: Potential role of TGF-beta in diabetic nephropathy. Miner Electrolyte Metab 24: 190–196, 1998[CrossRef][Medline]
  27. Isono M, Cruz MCI-DL, Chen S, Hong SW, Ziyadeh FN: Extracellular signal-regulated kinase mediates stimulation of TGF-beta1 and matrix by high glucose in mesangial cells. J Am Soc Nephrol 11: 2222–2230, 2000[Abstract/Free Full Text]
  28. Chen S, Jim B, Ziyadeh F: Diabetic nephropathy and transforming growth factor-beta: Transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol 23: 532–543, 2003[CrossRef][Medline]
  29. Wolf G, Ziyadeh F: The role of angiotensin II in diabetic nephropathy: Emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 29: 153–163, 1997[Medline]
  30. Singh R, Sing A, Alavi N, Leehey D: Mechanism of increased angiotensin II levels in glomerular mesangial cells cultured in high glucose. J Am Soc Nephrol 14: 873–880, 2003[Abstract/Free Full Text]
  31. Hoffman B, Sharma K, Zhu Y, Ziyadeh FN: Transcriptional activation of transforming growth factor-beta1 in mesangial cell culture by high glucose concentration. Kidney Int 54: 1107–1116, 1998[CrossRef][Medline]
  32. Hsieh T, Zhang S, Filep J, Tang S, Ingelfinger J, Chan J: High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 143: 2975–2986, 2002[Abstract/Free Full Text]
  33. Kiritoshi S, Nishikawa T, Sonoda K, Kukidome D, Senokuchi T, Matsuo T, Matsumara T, Tokunaga H, Brownlee M, Araki E: Reactive oxygen species from mitochondria induce cycloxygenase-2 gene expression in human mesangial cells. Diabetes 52: 2570–2577, 2003[Abstract/Free Full Text]
  34. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820, 2001[CrossRef][Medline]
  35. Chen J, Muntner P, Hamm L, Jones D, Batuman V, Fonseca V, Whelton, P, He J: The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 140: 167–174, 2004[Abstract/Free Full Text]
  36. Park Y, Zhu S, Palaniappan L, Heshka S, Carnethon, M, Heymsfield S: The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 163: 427–436, 2003[Abstract/Free Full Text]
  37. Ceriello A, Bortolotti N, Motz E, Crescentini A, Lizzio S, Russo A, Tonutti L, Taboga C: Meal-generated oxidative stress in type 2 diabetic patients. Diabetes Care 21: 1529–1533, 1998[Abstract]
  38. Coutinho M, Gerstein H, Wang Y, Yusuf S: The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 22: 233–240, 1999[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
Q. Dai, Y.-T. Gao, X.-O. Shu, G. Yang, G. Milne, Q. Cai, W. Wen, N. Rothman, H. Cai, H. Li, et al.
Oxidative Stress, Obesity, and Breast Cancer Risk: Results From the Shanghai Women's Health Study
J. Clin. Oncol., May 20, 2009; 27(15): 2482 - 2488.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
CJN.00990905v1
1/2/263    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McGowan, T. A.
Right arrow Articles by Sharma, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McGowan, T. A.
Right arrow Articles by Sharma, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS