AJP - Renal Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 293: F1256-F1261, 2007. First published August 1, 2007; doi:10.1152/ajprenal.00181.2007
0363-6127/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/4/F1256    most recent
00181.2007v1
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 Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gersch, M. S.
Right arrow Articles by Nakagawa, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gersch, M. S.
Right arrow Articles by Nakagawa, T.

Fructose, but not dextrose, accelerates the progression of chronic kidney disease

Michael S. Gersch,1,2 Wei Mu,1 Pietro Cirillo,1 Sirirat Reungjui,1 Li Zhang,1 Carlos Roncal,1 Yuri Y. Sautin,1 Richard J. Johnson,1 and Takahiko Nakagawa1

1Division of Nephrology, Dialysis, and Transplantation, University of Florida; and 2North Florida/South Georgia Veterans Health System, Gainesville, Florida

Submitted 16 April 2007 ; accepted in final form 27 July 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The metabolic syndrome has recently been recognized as a risk factor for kidney disease, but the mechanisms mediating this risk remain unclear. High fructose consumption by animals produces a model of the metabolic syndrome with hypertension, hyperlipidemia, and insulin resistance. The present study was conducted to test the hypothesis that consumption of a high-fructose diet could accelerate the progression of chronic kidney disease. Three groups of 14 male Sprague-Dawley rats were pair fed a specialized diet containing 60% fructose (FRU) or 60% dextrose (DEX) or standard rat chow (CON). After the animals were fed their assigned diet for 6 wk, five-sixths nephrectomy was performed, and the assigned diet was continued for 11 wk. Proteinuria was significantly increased and creatinine clearance was decreased in the FRU group compared with the CON and DEX groups, and blood urea nitrogen was higher in the FRU group than in the CON and DEX groups. Kidneys from the FRU group were markedly larger than kidneys from the CON and DEX groups. Glomerular sclerosis, tubular atrophy, tubular dilatation, and cellular infiltration appeared markedly worse in kidneys from the FRU group than in kidneys from the DEX and CON groups. Monocyte chemoattractant protein-1 (MCP-1) was measured in renal tissue homogenate and found to be increased in the FRU group. In vitro studies were conducted to determine the mechanism for increased renal MCP-1, and fructose stimulation of proximal tubular cells resulted in production of MCP-1. In conclusion, consumption of a high-fructose diet greatly accelerates progression of chronic kidney disease in the rat remnant kidney model.

metabolic syndrome; high-fructose corn syrup; monocyte chemoattractant protein-1

ACCORDING TO THE Third National Health and Nutrition Examination Survey data, 5,000,000-20,000,000 people in the United States have chronic kidney disease (CKD) (9). Physicians counsel these patients to follow various combinations of low-salt, low-fat, low-potassium, low-phosphate, and low-protein diets (23). However, patients are not routinely counseled regarding fructose consumption. Fructose has been recommended to diabetic patients, inasmuch as it does not elevate blood glucose levels (1, 6, 32). However, several researchers have raised the concern that fructose may contribute to the current epidemic of the metabolic syndrome (4, 17, 24, 28). A model commonly used in the literature to study the metabolic syndrome is fructose feeding. Rats that consume a high-fructose diet for 6 wk develop insulin resistance (11, 15), dyslipidemia (2, 8, 21, 22, 29, 37), hypertension (14, 15, 33), and hyperuricemia (27, 30). Fructose feeding in mice has been shown to lead to the development of obesity as well (18).

The metabolic syndrome is a well-established risk factor for diabetes, cardiovascular disease, and mortality. Recently, several studies have suggested that the metabolic syndrome may also contribute to the development of CKD. Using the Third National Health and Nutrition Examination Survey database, Chen et al. (7) showed an independent association of the metabolic syndrome with CKD. Expanding on this work, Kurella et al. (25) showed that the metabolic syndrome increased the risk of developing new-onset CKD in the Atherosclerosis Risk in Communities Study. Renal injury is also seen in other animal models of the metabolic syndrome, including Zucker fatty diabetic rats (10) and db/db mice (38).

Fructose consumption has steadily increased over the past 30 years in parallel to the growth of the obesity/metabolic syndrome epidemic, and fructose and high-fructose corn syrup are ingredients in many commercially produced food products (1). In fact, the average American now consumes 64 pounds of sweeteners every year (12). If we consider the animal and epidemiological data, it is reasonable to hypothesize that fructose consumption in our diet may be among the factors that contribute to the epidemic of the metabolic syndrome and, consequently, to the epidemic of chronic renal disease (1, 11, 17, 18, 27, 28). Importantly, fructose consumption by our CKD patients may actually be placing them at an increased risk for progression of their CKD. Despite the public health importance of this issue, little research exists on the long-term effects of fructose consumption in CKD patients. Thus we designed the present experiment to examine the effects of fructose feeding on the progression of chronic renal disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
All animal protocols were approved by the University of Florida Institutional Animal Care and Use Committee. Forty-two 150-g male Sprague-Dawley rats (Charles Rivers Laboratories, Wilmington, MA) were randomized to receive a diet of 60% fructose, 60% dextrose, or the standard rat chow, which contains complex carbohydrates, instead of purified sugars (Harlan-Teklad, Madison, WI). The animals were pair fed to eliminate animal weight as a variable in the study. Weights were obtained weekly. Animals were maintained in temperature- and humidity-controlled specific pathogen-free conditions on a 12:12-h light-dark cycle. After 6 wk, the animals were anesthetized with isoflurane, and a left nephrectomy and two-thirds right nephrectomy were performed by the polectomy method, as previously described (19). Four animals died from complications related to the surgical procedure within 2 wk of the surgery and were excluded from the analysis. The assigned diets were continued for 11 wk, and then the animals were killed. Fasting blood samples for analysis were obtained by tail vein sampling 1 wk before remnant kidney (RK) surgery and 2, 7, and 11 wk after RK surgery. Metabolic cages were used for collection of urine samples 8 wk after RK surgery. Blood pressure was measured by the tail cuff method 8 wk after RK surgery (15).

Renal histology. Tissue was fixed in methyl-Carnoy solution, dehydrated in alcohols, and embedded in paraffin (Sigma-Aldrich, St. Louis, MO), and 2-µm sections were obtained. Tissue was stained with periodic acid-Schiff (PAS) stain, as previously described (19). Glomerular sclerosis and tubulointerstitial injury were scored using PAS-stained sections. All glomeruli in each section were counted. The percentage of glomeruli demonstrating sclerosis, defined as accumulation of hyaline material and collapse of the capillary loops, was calculated. Tubular interstitial injury was scored on a scale of 0–5 as follows (see Table 4). {alpha}-Smooth muscle actin ({alpha}-SMA) was stained as previously described (19) with {alpha}-SM1 (Sigma; 1:100 dilution) for detection of vascular disease as well as myofibroblast formation. Osteopontin, a marker of tubular damage (36), was stained using a goat anti-osteopontin antibody (obtained from C. Giachelli, University of Washington, Seattle, WA). Collagen type IV was stained with an antibody obtained from Southern Biotechnology (Birmingham, AL). {alpha}-SMA, collagen, and osteopontin staining were quantified after examination of ≥40 fields at x400 magnification by a scoring method similar to that used for tubulointerstitial injury (see Table 4), as previously described (19). Macrophages were stained with ED-1 (Serotec, Indianapolis, IN). ED-1-positive cells were counted in 40 nonconsecutive fields at x400 magnification. Areas with extensive scarring from surgery were avoided. Biochemistries were tested with the VetAce machine (Alpha Wasserman, West Caldwell, NJ).


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

  		Table 4. Renal histological scoring of CKD progression by fructose feeding

 
ELISA for monocyte chemoattractant protein-1. Tissue homogenates were prepared by mechanical homogenization after addition of fresh tissue to RIPA buffer (Sigma-Aldrich) to which Compete (Roche, Mannheim, Germany) protease inhibitors were added. Samples were incubated at 4°C for 1 h and then centrifuged at 4°C at 16,000 g for 60 min. The supernatant was removed, and the protein concentration was standardized at 8 mg/ml after total protein measurement (Pierce, Rockford, IL). Rat monocyte chemoattractant protein-1 (MCP-1) protein was measured on these homogenates by ELISA with a kit (BD Biosciences Pharmingen, San Diego, CA) according to the manufacturer's directions.

Cell culture. Human kidney proximal tubular (HK-2) cells, an immortalized proximal tubular epithelial cell line from normal adult human kidney, were obtained from American Type Culture Collection (Rockville, MD). Cells were grown to confluence in DMEM-nutrient mix (50:50) F-12 (DMEM-F-12) with L-glutamine and HEPES buffer (Invitrogen, Carlsbad, CA) supplemented with 10% FBS, 100 U/ml penicillin, 100 g/ml streptomycin, and 1% insulin-transferrin-selenium (Invitrogen). Cells were plated in 24-well plates and cultured at 37°C in 95% air-5% CO2 up to 70–75% of confluence and then stimulated with 5, 10, and 15 mM fructose for 72 h in glucose-free DMEM supplemented with 5 mM glucose and 10% dialyzed FBS. After 72 h, the supernatants were collected, and human MCP-1 concentration was measured with a kit (R & D) according to the manufacturer's directions. The volume of supernatants was measured, and total MCP-1 secreted was calculated and then normalized to cell number determined by measurement of cellular DNA with CyQUANT assay (Invitrogen).

Statistics. Values are means ± SE. Statistics were analyzed with one-way ANOVA and Student's t-test as appropriate. Significance defined as P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
During the study, three animals in the fructose group died as a result of progressive kidney disease, whereas no animals in the normal or dextrose groups died. Renal function of animals treated with fructose or dextrose 6 wk before RK surgery was not different from renal function of animals fed the normal diet (Table 1). However, by 11 wk after RK surgery, renal function, as measured by serum blood urea nitrogen (BUN) and a trend, which did not quite reach statistical significance, toward an increased creatinine level, deteriorated significantly in fructose-treated, but not in dextrose-treated, animals (P = 0.09, normal vs. dextrose; Table 2). By 8 wk after the RK procedure, proteinuria was significantly increased and measured creatinine clearance was significantly decreased in fructose-fed animals (Table 3).


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

  		Table 1. Fructose feeding results in development of traits of the metabolic syndrome

 

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

  		Table 2. Serum biochemistry assessment of acceleration of CKD progression by fructose feeding after RK surgery

 

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

  		Table 3. Urinary protein and creatinine clearance assessment of acceleration of CKD progression by fructose feeding

 
There was no statistically significant difference in blood pressure between the three groups at 9 wk or at the end of the study; however, there was a trend that did not reach statistical significance for higher blood pressure in the fructose-fed animals: 158 ± 1, 156 ± 2, and 166 ± 3 mmHg in normal, dextrose-fed, and fructose-fed groups, respectively (P = 0.3). Throughout the study, there were no significant differences in the animals’ weights between the groups at any of the time points (data not shown).

Grossly, kidneys from the fructose-fed animals were markedly larger than those from the normal or dextrose-fed animals: 3.4 ± 0.03, 2.6 ± 0.2, and 4.9 ± 0.3 g kidney/kg body wt in normal, dextrose-fed, and fructose-fed animals, respectively (P < 0.05; Fig. 1). PAS staining showed significantly more glomerulosclerosis and tubulointerstitial injury in the fructose-fed group (Table 4, Fig. 2). Additionally, more tubular damage, such as dilatation, atrophy, and epithelial cell proliferation, was observed in fructose-fed animals. These damaged tubules expressed osteopontin (Table 4, Fig. 2). On the other hand, myofibroblast formation from interstitial fibroblasts was also induced in fructose-treated animals, as evidenced by {alpha}-SMA staining (Table 4, Fig. 2). Interstitial collagen deposition was also increased in animals fed fructose compared with animals fed dextrose or a normal diet (Table 4). More macrophage infiltration, as evidenced by infiltration of ED-1-positive cells, was observed in fructose-fed animals (Table 4, Fig. 2).


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 1. Kidney weight (g) normalized to animal body weight (kg) in a remnant kidney (RK) model in which animals were fed 60% fructose, control (normal), or 60% dextrose diet. Fructose-fed animals developed renal hypertrophy.

 

Figure 2
View larger version (119K):
[in this window]
[in a new window]

  		Fig. 2. Fructose consumption accelerates progression of chronic kidney disease (CKD) as assessed by renal histology. Renal tissue was obtained 11 wk after surgery from RK animals fed normal, 60% dextrose, or 60% fructose diet for 6 wk. Periodic acid-Schiff (PAS) staining shows marked glomerular hypertrophy, glomerular sclerosis, and interstitial damage in fructose-fed animals. Magnification x400. {alpha}-Smooth muscle actin (ASMA) staining shows marked expression of {alpha}-SMA in fructose-fed animals consistent with increased myofibroblast formation. Magnification x400. Osteopontin staining shows marked increase in osteopontin staining in fructose-fed animals consistent with increased tubular damage. Magnification x200. ED-1 staining shows increased ED-1-positive cells in fructose-fed animals consistent with increased infiltration of macrophages. Magnification x600.

 
To explain the increased numbers of macrophages in the kidneys from the fructose-treated animals, MCP-1 levels were measured in renal homogenates. MCP-1 was significantly increased in the fructose-fed animals compared with animals fed the normal or the dextrose diet (Fig. 3).


Figure 3
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 3. Monocyte chemoattractant protein-1 (MCP-1) levels are higher in renal tissue from animals fed fructose than in animals fed dextrose or normal diet. Tissue homogenate MCP-1 levels were determined by ELISA. Values are means ± SE. NS, not significant.

 
To determine whether the increase in renal MCP-1 was due to fructose exposure or differences in the underlying kidney disease, HK-2 cells were stimulated with fructose in vitro. Stimulation of HK-2 cells with low doses of fructose resulted in a dose-dependent increase in production of MCP-1 normalized to cell number by total DNA content of the cells (Fig. 4). Stimulation of HK-2 cells with fructose did not result in HK-2 cell proliferation or increased cell death (data not shown).


Figure 4
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 4. Fructose stimulates production of MCP-1 in HK-2 cells. HK-2 cells were stimulated for 72 h in medium containing 0, 5, 10, and 15 mM fructose. Total MCP-1 in supernatant was normalized for cell number by amount of DNA in each well. Values are means ± SE. P = 0.001 (1-way ANOVA).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we have shown that fructose consumption accelerates the progression of CKD in the rodent RK model. Fructose-treated animals had greater protein excretion, higher serum BUN and creatinine, decreased creatinine clearance, more renal hypertrophy, and higher mortality. The difference in serum creatinine did not reach statistical significance; however, serum creatinine is not a very sensitive marker of renal damage (13). Histologically, the kidneys from the fructose-treated animals showed more glomerulosclerosis, tubular dilatation, tubular atrophy, interstitial inflammation, myofibroblasts, tubular osteopontin, interstitial collagen, and ED-1-positive cells.

This is the first study showing that fructose consumption can accelerate the progression of chronic renal disease. Previously, fructose was reported to cause glomerular hypertrophy and subtle renal damage (3). More recently, it was reported that consumption of fructose induces glomerular hypertension and sclerosis of the afferent arteriole (30). In the present study, the dextrose-fed animals did not develop worse renal disease than the control animals, because glucose consumption did not result in systemic hyperglycemia in these nondiabetic animals.

Indirectly, fructose consumption could lead to the progression of CKD by causing hypertension. However, in the present study, all the RK animals developed hypertension, and there was no statistically significant difference in blood pressure between groups. Thus the increased renal injury in the fructose-treated group was unlikely to be primarily a blood pressure effect, although it is possible that the trend toward a higher blood pressure in the fructose-fed animals contributed to some of the progression of kidney disease. The hypertensive effects of fructose feeding may have been masked by the underlying hypertension induced by the RK surgery.

Several mechanisms explain how the metabolic syndrome could contribute to the development of CKD: induction of endothelial dysfunction, oxidative stress, hemodynamic alterations, proinflammatory environment, lipotoxicity, and hyperuricemia (31). Hyperinsulinemia may have also played a role in progression of kidney disease in this model. In the present study, insulin levels were elevated, and it is known that treatment with troglitazone to correct hyperinsulinemia slows progression of kidney disease (35). Lipotoxicity is an attractive mechanism, inasmuch as the cholesterol derangements in fructose feeding are striking, and treatment with statins has been shown to slow the progression of kidney disease in the RK model (20). However, fructose may also have direct toxic effects on the renal tubular cells, as evidenced by the marked tubular changes and {alpha}-SMA and osteopontin expression by tubular cells. Renal tubular cells are known to express the fructose transporter GLUT-5, as well as the enzymes necessary for glucose metabolism (26). Further studies are needed to determine mechanistically how fructose may lead to tubular cell damage.

An increase in ED-1-positive cells was noted in the renal cortex from animals treated with fructose. ED-1 antibody stains tissue monocytes and macrophages. Because monocytes were increased in the kidneys from fructose-treated animals, we examined the level of MCP-1 in the renal cortex. We found that MCP-1 was elevated in the fructose-treated animals. This led to the cell culture studies showing that fructose stimulated MCP-1 production in HK-2 cells. In these studies, MCP-1 production was normalized for cell number by the amount of DNA in the cells. This technique was preferred over measurement of protein content of the cell lysate, inasmuch as stimulation with sugars can result in cell hypertrophy. Measurement of DNA content in the cells also allowed us to demonstrate that the fructose stimulation did not result in proliferation or death of the HK-2 cells.

Fructose feeding has been reported to result in hyperuricemia (33, 34); however, this was not detected in the present study. Because hyperuricemia is greatest 50–200 min after after fructose consumption (5), this effect may be missed in fasting samples. Fasting samples were collected for measurement of fasting insulin and triglyceride concentrations.

The 60% fructose diet utilized in the present study is the classical model of fructose-induced metabolic syndrome described in the literature (2, 8, 14–16, 27). Although this is four times the amount of fructose that many people are consuming in their diet, in animal experiments, it is common practice to use higher-dose treatments to achieve a statistically significant result in a very limited time frame. This experiment was conducted over only a few months, whereas patients are more likely to have CKD for many years. Recently, Sanchez-Lozada et al. (30) reported the induction of the metabolic syndrome after 6 wk of feeding a diet of only 30% fructose. More studies are needed to determine whether lower doses of fructose, administered over a longer time period, also lead to the progression of CKD.

In conclusion, we have shown that consumption of a high-fructose diet accelerates the progression of CKD. Over the past 30 years, fructose has become a standard part of the American diet. It is possible the fructose consumption by our patients may be contributing to the development or progression of CKD. If this is the case, restriction of dietary fructose may slow the progression of CKD in these patients. More studies are needed to explore the pathophysiological mechanisms underlying this important public health issue.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grant HL-68607 and the Gatorade Foundation.


   DISCLOSURES
 
R. J. Johnson is a consultant for Nephronomics. R. J. Johnson and T. Nakagawa are listed as inventors on patent applications by the University of Florida related to the role of fructose in hypertension and metabolic syndrome.


   ACKNOWLEDGMENTS
 
This work was presented as an abstract at the American Society of Nephrology Meeting in November 2006.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. S. Gersch, 1600 SW Archer Rd., Rm. CG 98, PO Box 100224, Gainesville, FL 32610-0224 (e-mail: gerscms{at}medicine.ufl.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bantle JP. Is fructose the optimal low glycemic index sweetener? Nestle Nutr Workshop Ser Clin Perform Programme 11: 83–95, 2006.[Medline]
  2. Bar-On H, Stein Y. Effect of glucose and fructose administration on lipid metabolism in the rat. J Nutr 94: 95–105, 1968.[Abstract/Free Full Text]
  3. Boot-Handford RP, Heath H. The effect of dietary fructose and diabetes on the rat kidney. Br J Exp Pathol 62: 398–406, 1981.[Web of Science][Medline]
  4. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79: 537–543, 2004.[Abstract/Free Full Text]
  5. Buemann B, Toubro S, Holst JJ, Rehfeld JF, Bibby BM, Astrup A. d-Tagatose, a stereoisomer of d-fructose, increases blood uric acid concentration. Metabolism 49: 969–976, 2000.[CrossRef][Web of Science][Medline]
  6. Bukar J, Mezitis NH, Saitas V, Pi-Sunyer FX. Frozen desserts and glycemic response in well-controlled NIDDM patients. Diabetes Care 13: 382–385, 1990.[Abstract]
  7. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J. The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 140: 167–174, 2004.[Abstract/Free Full Text]
  8. Cohen AM, Teitelbaum A. Effect of glucose, fructose, sucrose and starch on lipogenesis in rats. Life Sci 7: 23–29, 1968.[CrossRef][Web of Science][Medline]
  9. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41: 1–12, 2003.[Web of Science][Medline]
  10. Dominguez JH, Wu P, Hawes JW, Deeg M, Walsh J, Packer SC, Nagase M, Temm C, Goss E, Peterson R. Renal injury: similarities and differences in male and female rats with the metabolic syndrome. Kidney Int 69: 1969–1976, 2006.[CrossRef][Web of Science][Medline]
  11. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr 76: 911–922, 2002.[Abstract/Free Full Text]
  12. Guthrie JF, Morton JF. Food sources of added sweeteners in the diets of Americans. J Am Diet Assoc 100: 43–51, 2000.[CrossRef][Web of Science][Medline]
  13. Hewitt SM, Dear J, Star RA. Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol 15: 1677–1689, 2004.[Abstract/Free Full Text]
  14. Huang YJ, Fang VS, Juan CC, Chou YC, Kwok CF, Ho LT. Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation. Metabolism 46: 1252–1258, 1997.[CrossRef][Web of Science][Medline]
  15. Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension 10: 512–516, 1987.[Abstract/Free Full Text]
  16. Hwang IS, Huang WC, Wu JN, Shian LR, Reaven GM. Effect of fructose-induced hypertension on the renin-angiotensin-aldosterone system and atrial natriuretic factor. Am J Hypertens 2: 424–427, 1989.[Web of Science][Medline]
  17. Jacobson MF. High-fructose corn syrup and the obesity epidemic. Am J Clin Nutr 80: 1081–1082, 2004.[Free Full Text]
  18. Jurgens H, Haass W, Castaneda TR, Schurmann A, Koebnick C, Dombrowski F, Otto B, Nawrocki AR, Scherer PE, Spranger J, Ristow M, Joost HG, Havel PJ, Tschop MH. Consuming fructose-sweetened beverages increases body adiposity in mice. Obes Res 13: 1146–1156, 2005.[Web of Science][Medline]
  19. Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13: 2888–2897, 2002.[Abstract/Free Full Text]
  20. Kasiske BL, O'Donnell MP, Garvis WJ, Keane WF. Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res 62: 367–374, 1988.[Abstract/Free Full Text]
  21. Kaufmann NA, Poznanski R, Blondheim SH, Stein Y. Comparison of effects of fructose, sucrose, glucose, and starch on serum lipids in patients with hypertriglyceridemia and normal subjects. Am J Clin Nutr 20: 131–132, 1967.[Web of Science][Medline]
  22. Kaufmann NA, Poznanski R, Blondheim SH, Stein Y. Effect of fructose, glucose, sucrose and starch on serum lipids in carbohydrate induced hypertriglyceridemia and in normal subjects. Isr J Med Sci 2: 715–726, 1966.[Web of Science][Medline]
  23. Klahr S. The modification of diet in renal disease study. N Engl J Med 320: 864–866, 1989.[Web of Science][Medline]
  24. Krilanovich NJ. Fructose misuse, the obesity epidemic, the special problems of the child, and a call to action. Am J Clin Nutr 80: 1446–1448, 2004.[Free Full Text]
  25. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 16: 2134–2140, 2005.[Abstract/Free Full Text]
  26. Mantych GJ, James DE, Devaskar SU. Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier. Endocrinology 132: 35–40, 1993.[Abstract/Free Full Text]
  27. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290: F625–F631, 2006.[Abstract/Free Full Text]
  28. Nakagawa T, Tuttle KR, Short RA, Johnson RJ. Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 1: 80–86, 2005.[CrossRef][Web of Science][Medline]
  29. Nikkila EA, Ojala K. Acute effects of fructose and glucose on the concentration and removal rate of plasma triglyceride. Life Sci 5: 89–94, 1966.[CrossRef][Medline]
  30. Sanchez-Lozada LG, Tapia E, Jimenez A, Bautista P, Cristobal M, Nepomuceno T, Soto V, Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am J Physiol Renal Physiol 292: F423–F429, 2007.[Abstract/Free Full Text]
  31. Sarafidis PA, Ruilope LM. Insulin resistance, hyperinsulinemia, and renal injury: mechanisms and implications. Am J Nephrol 26: 232–244, 2006.[CrossRef][Web of Science][Medline]
  32. Uusitupa MI. Fructose in the diabetic diet. Am J Clin Nutr 59: 753S–757S, 1994.[Medline]
  33. Vasdev S, Longerich L, Gill V. Prevention of fructose-induced hypertension by dietary vitamins. Clin Biochem 37: 1–9, 2004.[CrossRef][Web of Science][Medline]
  34. Wang YM, van Eys J. Nutritional significance of fructose and sugar alcohols. Annu Rev Nutr 1: 437–475, 1981.[CrossRef][Web of Science][Medline]
  35. Yoshida K, Kohzuki M, Xu HL, Wu XM, Kamimoto M, Sato T. Effects of troglitazone and temocapril in spontaneously hypertensive rats with chronic renal failure. J Hypertens 19: 503–510, 2001.[CrossRef][Web of Science][Medline]
  36. Yu XQ, Fan JM, Nikolic-Paterson DJ, Yang N, Mu W, Pichler R, Johnson RJ, Atkins RC, Lan HY. IL-1 up-regulates osteopontin expression in experimental crescentic glomerulonephritis in the rat. Am J Pathol 154: 833–841, 1999.[Abstract/Free Full Text]
  37. Zakim D, Pardini R, Herman RH, Sauberlich H. The relation of hepatic {alpha}-glycerophosphate concentration to lipogenesis in rat liver. Biochim Biophys Acta 137: 179–180, 1967.[Medline]
  38. Ziyadeh FN, Hoffman BB, Han DC, Iglesias-de la Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti-transforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci USA 97: 8015–8020, 2000.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Renal Physiol.Home page
Q.-H. Hu, C. Wang, J.-M. Li, D.-M. Zhang, and L.-D. Kong
Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement
Am J Physiol Renal Physiol, October 1, 2009; 297(4): F1080 - F1091.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
P. Cirillo, Y. Y. Sautin, J. Kanellis, D.-H. Kang, L. Gesualdo, T. Nakagawa, and R. J. Johnson
Systemic inflammation, metabolic syndrome and progressive renal disease
Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1384 - 1387.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
P. Cirillo, M. S. Gersch, W. Mu, P. M. Scherer, K. M. Kim, L. Gesualdo, G. N. Henderson, R. J. Johnson, and Y. Y. Sautin
Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells
J. Am. Soc. Nephrol., March 1, 2009; 20(3): 545 - 553.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. E. Choi
The Not-so-Sweet Side of Fructose
J. Am. Soc. Nephrol., March 1, 2009; 20(3): 457 - 459.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
O. Glushakova, T. Kosugi, C. Roncal, W. Mu, M. Heinig, P. Cirillo, L. G. Sanchez-Lozada, R. J. Johnson, and T. Nakagawa
Fructose Induces the Inflammatory Molecule ICAM-1 in Endothelial Cells
J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1712 - 1720.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/4/F1256    most recent
00181.2007v1
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 Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gersch, M. S.
Right arrow Articles by Nakagawa, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gersch, M. S.
Right arrow Articles by Nakagawa, T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.