Restricted intake of dietary advanced glycation end products retards renal progression in the remnant kidney model
2007; Elsevier BV; Volume: 71; Issue: 9 Linguagem: Inglês
10.1038/sj.ki.5002162
ISSN1523-1755
AutoresJianxun Feng, Fan Fan Hou, Mingshuang Liang, G.B. Wang, Xiaomei Zhang, H.Y. Li, Di Xie, Jianwei Tian, Zhenyin Liu,
Tópico(s)Dialysis and Renal Disease Management
ResumoDiet-derived advanced glycation end products (AGEs) contribute significantly to accumulation of AGEs in renal insufficiency. To test whether modulation of dietary AGEs would impact on progression of chronic renal disease, 5/6 nephrectomy rats were randomly placed on three diets that differed only in AGEs content (low AGEs diet (LAD), high AGEs diet (HAD), and standard rodent diet (SRD)) for 5–13 weeks. Compared with SRD- or HAD-fed rats, LAD-treated animals showed decreased proteinuria and retarded decline of creatinine clearance without alteration of blood pressure. Glomerular volume was reduced by 23% compared with HAD-fed rats at week 13 (P<0.001). Renal fibrosis progressed with time in the remnant kidneys from HAD-fed rats. However, LAD-fed animals presented a better-preserved structure of the kidneys. LAD-fed rats demonstrated significantly decreased serum and renal AGEs concentration (P<0.01 and P<0.01). This was associated with marked decrease of intrarenal advanced oxidation protein products and thiobarbituric acid reactive substances, as well as increase of glutathione peroxidase activity. LAD treatment also downregulated expression of monocyte chemoattractant protein-1 and transforming growth factor-β1 and ameliorated macrophage infiltration in the remnant kidney. These results demonstrated that restriction of dietary AGEs intake retards progression of renal fibrosis and dysfunction in the remnant kidney model. Diet-derived advanced glycation end products (AGEs) contribute significantly to accumulation of AGEs in renal insufficiency. To test whether modulation of dietary AGEs would impact on progression of chronic renal disease, 5/6 nephrectomy rats were randomly placed on three diets that differed only in AGEs content (low AGEs diet (LAD), high AGEs diet (HAD), and standard rodent diet (SRD)) for 5–13 weeks. Compared with SRD- or HAD-fed rats, LAD-treated animals showed decreased proteinuria and retarded decline of creatinine clearance without alteration of blood pressure. Glomerular volume was reduced by 23% compared with HAD-fed rats at week 13 (P<0.001). Renal fibrosis progressed with time in the remnant kidneys from HAD-fed rats. However, LAD-fed animals presented a better-preserved structure of the kidneys. LAD-fed rats demonstrated significantly decreased serum and renal AGEs concentration (P<0.01 and P<0.01). This was associated with marked decrease of intrarenal advanced oxidation protein products and thiobarbituric acid reactive substances, as well as increase of glutathione peroxidase activity. LAD treatment also downregulated expression of monocyte chemoattractant protein-1 and transforming growth factor-β1 and ameliorated macrophage infiltration in the remnant kidney. These results demonstrated that restriction of dietary AGEs intake retards progression of renal fibrosis and dysfunction in the remnant kidney model. Chronic kidney disease (CKD) is a significant interactive disease in patients with diabetes, hypertension, and cardiovascular disease with major morbidity consequences and high costs to the healthcare system.1.Collins A.J. Couser W.G. Dirks J.H. et al.World kidney day: an idea whose time has come.Kidney Int. 2006; 69: 781-782Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Renal fibrosis, the final common pathway of CKD, predicts the degree of renal dysfunction and long-term prognosis for almost all forms of CKD. Numerous mechanisms have been implicated in the initiation of this cascade including activation of renin-angiotensin system, overexpression of cytokines, redox imbalance, and metabolic toxins accumulation.2.Eddy A.A. Molecular insights into renal interstitial fibrosis.J Am Soc Nephrol. 1996; 7: 2495-2508Crossref PubMed Google Scholar Advanced glycation end products (AGEs) might be one of these toxins. Endogenous AGEs are formed during nonenzymatic reaction between protein and glucose or glucose degradation products under hyperglycemia.3.Vlassara H. Palace M.R. Diabetes and advanced glycation end products.J Intern Med. 2002; 251: 87-101Crossref PubMed Scopus (581) Google Scholar,4.Schleicher E.D. Wagner E. Nerlich A.G. Increased accumulation of the glycoxidation product N (epsilon)-(carboxymethyl) lysine in human tissues in diabetes and aging.J Clin Invest. 1997; 99: 457-468Crossref PubMed Scopus (637) Google Scholar Increased AGEs burden has also been demonstrated in euglycemic patients with renal insufficiency, in whom AGEs accumulation is attributed to either decreased renal clearance or increased formation of these compounds owing to enhanced oxidative stress.5.Miyata T. Kurokawa K. van Ypersele de Strihou C. Relevance of oxidative and carbonyl stress to long-term uremic complications.Kidney Int. 2000; 76: S120-S125Abstract Full Text Full Text PDF Scopus (122) Google Scholar,6.Weiss M.F. Erhard P. Kader-Attia F.A. et al.Mechanisms for the formation of glycoxidation products in end-stage renal disease.Kidney Int. 2000; 57: 2571-2585Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar In addition to those endogenously formed, AGEs are abundant in exogenous sources such as foods, especially when prepared under elevated temperature.7.Henle T. AGEs in foods: do they play a role in uremia?.Kidney Int. 2003; 84: 145-147Abstract Full Text Full Text PDF Scopus (146) Google Scholar Modulation of dietary AGEs in human subjects or animals with or without diabetes or renal disease modifies circulating AGEs levels, suggesting that dietary AGEs intake constitutes an important source of the body AGEs pool.8.Hofmann S.M. Dong H.J. Li Z. et al.Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse.Diabetes. 2002; 51: 2082-2089Crossref PubMed Scopus (248) Google Scholar,9.Uribarri J. Peppa M. Cai W. et al.Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients.J Am Soc Nephrol. 2003; 14: 728-731Crossref PubMed Scopus (273) Google Scholar It has been documented that AGEs, both endogenously formed and exogenously ingested, are bioreactive toxins8.Hofmann S.M. Dong H.J. Li Z. et al.Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse.Diabetes. 2002; 51: 2082-2089Crossref PubMed Scopus (248) Google Scholar, 10.Raj D.S. Choudhury D. Welbourne T.C. Levi M. Advanced glycation end products: a Nephrologist's perspective.Am J Kidney Dis. 2000; 35: 365-380Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 11.Hou F.F. Owen Jr, W.F. Beta 2-microglobulin amyloidosis: role of monocytes/macrophages.Curr Opin Nephrol Hypertens. 2002; 11: 417-421Crossref PubMed Scopus (16) Google Scholar and contribute to the complications of diabetes and renal insufficiency, such as endothelial dysfunction, accelerated atherosclerosis, and β2-microglobulin amyloidosis.10.Raj D.S. Choudhury D. Welbourne T.C. Levi M. Advanced glycation end products: a Nephrologist's perspective.Am J Kidney Dis. 2000; 35: 365-380Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 11.Hou F.F. Owen Jr, W.F. Beta 2-microglobulin amyloidosis: role of monocytes/macrophages.Curr Opin Nephrol Hypertens. 2002; 11: 417-421Crossref PubMed Scopus (16) Google Scholar, 12.Hou F.F. Miyata T. Boyce J. et al.Beta(2)-microglobulin modified with advanced glycation end products delays monocyte apoptosis.Kidney Int. 2001; 59: 990-1002Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Prolonged intravenous injection of pre-formed AGEs into normal animals results in albuminuria and glomerular sclerosis,13.Vlassara H. Striker L.J. Teichberg S. et al.Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats.Proc Natl Acad Sci USA. 1994; 91: 11704-11708Crossref PubMed Scopus (413) Google Scholar suggesting that AGEs might be a class of renal fibrogenic factors. Kidney is the major organ for dealing with the daily load of dietary AGEs7.Henle T. AGEs in foods: do they play a role in uremia?.Kidney Int. 2003; 84: 145-147Abstract Full Text Full Text PDF Scopus (146) Google Scholar,14.Foerster A. Henle T. Glycation in food and metabolic transit of dietary AGEs (advanced glycation end-products): studies on the urinary excretion of pyrraline.Biochem Soc Trans. 2003; 31: 1383-1385Crossref PubMed Google Scholar and the predominant tissue of AGEs accumulation after oral administration.15.Faist V. Wenzel E. Randel G. In vitro and in vivo studies on the metabolic transit of Nε-carboxymethyllysine.Czech J Food Sci. 2000; 18: 116-119Google Scholar Plasma AGEs levels are closely correlated with the progression of renal insufficiency.16.Hou F.F. Ren H. Owen Jr, W.F. et al.Enhanced expression of receptor for advanced glycation end products in chronic kidney disease.J Am Soc Nephrol. 2004; 15: 1889-1896Crossref PubMed Scopus (84) Google Scholar Thus, it is important to clarify whether accumulating dietary AGEs contribute significantly to the progression of CKD, especially in the presence of renal insufficiency. A short-term in vivo animal study has in part revealed this pathogenic link by showing that the administration of an AGEs-rich diet to the remnant kidney model for a short period (6 weeks) result in increase of proteinuria.17.Šebeková K. Faist V. Hofmann T. et al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model.Am J Kidney Dis. 2003; 41: S48-S51Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar However, the impact of prolonged load of dietary AGEs on the structure and function of the kidney, particularly in the presence of renal dysfunction, has remained unclear. This study was conducted to test the hypothesis that modulation of dietary AGEs intake may modify progression of CKD. As shown in Table 1, the three kinds of diet were nutritionally equivalent and differed only in AGEs content. As the daily food intake was equal between high AGEs diet (HAD)-, low AGEs diet (LAD)- and standard rodent diet (SRD)-fed groups (Figure 1a), HAD-fed animals ingested threefold more AGEs and LAD-fed rats ingested onefold less AGEs as compared with SRD-fed animals.Table 1Characteristic of the dietaNutrients were quantified by the Guangdong Province Institute of Animals Feed.HADLADSRDNutrients Protein (g/100 g)17.517.016.0 Fat (g/100 g)6.36.15.0 Carbohydrate (g/100 g)61.060.065.0 Fiber (g/100 g)2.52.62.4 Calcium (g/100 g)1.31.31.2 Phosphate (g/100 g)0.40.50.4 Soluble chloride (g/100 g)0.30.40.4 Lysine (g/100 g)0.80.80.7 Methionine (g/100 g)0.40.40.4 Vitamin A (IU/100 g)253240238 Vitamin D3 (IU/100 g)130120110 Vitamin E (IU/100 g)5.55.65.0Total calories (kcal/g)3.53.73.6AGEsbContent of AGEs was determined based on enzyme-linked immunosorbent assay using an anti-CML polyclonal antibody12,20 and on fluorospectrophotometry.19 CML(ng/mg)785112217 Total fluorescent AGEs (AU/mg)63.823.128.3AGEs, advanced glycation end products; CML, Nε-carboxymethyllysine; HAD, high-advanced glycation end products diet; LAD, low-advanced glycation end products diet; SRD, standard rodent diet.a Nutrients were quantified by the Guangdong Province Institute of Animals Feed.b Content of AGEs was determined based on enzyme-linked immunosorbent assay using an anti-CML polyclonal antibody12.Hou F.F. Miyata T. Boyce J. et al.Beta(2)-microglobulin modified with advanced glycation end products delays monocyte apoptosis.Kidney Int. 2001; 59: 990-1002Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,20.Cai W. Cao Q.D. Zhu L. et al.Oxidative stress-induced carbonyl compounds from common foods: novel mediators of cellular dysfunction.Mol Med. 2002; 8: 337-346PubMed Google Scholar and on fluorospectrophotometry.19.Fu M.X. Requena J.R. Jenkins A.J. et al.The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions.J Biol Chem. 1996; 271: 9982-9986Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar Open table in a new tab AGEs, advanced glycation end products; CML, Nε-carboxymethyllysine; HAD, high-advanced glycation end products diet; LAD, low-advanced glycation end products diet; SRD, standard rodent diet. Serum AGEs levels, assessed as Nε-carboxymethyllysine (CML)-like immunoepitopes, were significant higher in 5/6 nephrectomy (5/6 Nx) rats than the sham-operated controls (P<0.05). Animals given HAD showed marked increase of serum AGEs as compared with SRD-fed 5/6 Nx rats. LAD-treated rats had significant lower serum AGEs levels than SRD-fed 5/6 Nx animals (Figure 1b). A similar pattern was observed in AGEs levels in the remnant kidney among animals received three kinds of diet (Figure 1c). There was no significant difference in lipid profile and albumin levels among 5/6 Nx rats given food containing different levels of AGEs (Table 2).Table 2Serum lipid profile and albuminNTotal cholesterol (mmol/l)Triglycerides (mmol/l)Total protein (g/l)Albumin (g/l)HAD-fed 5/6 Nx rat103.03±0.301.42±0.2943.6±2.614.1±1.8LAD-fed 5/6 Nx rat102.51±0.601.25±0.2348.2±3.516.3±2.7SRD-fed 5/6 Nx rat102.75±0.15aP<0.05, compared with sham-operated control.1.34±0.20aP<0.05, compared with sham-operated control.47.4±2.615.5±2.5aP<0.05, compared with sham-operated control.Sham-operated control101.36±0.110.50±0.0257.6±3.027.1±1.4HAD, high-advanced glycation end products diet; LAD, low-advanced glycation end products diet; SRD, standard rodent diet; Nx, nephrectomy; N, number of rats.Data were mean±s.d. Blood samples were collected at week 13 of the study after overnight fast.a P<0.05, compared with sham-operated control. Open table in a new tab HAD, high-advanced glycation end products diet; LAD, low-advanced glycation end products diet; SRD, standard rodent diet; Nx, nephrectomy; N, number of rats. Data were mean±s.d. Blood samples were collected at week 13 of the study after overnight fast. As shown in Table 3, the weight of the remnant kidney increased with time in 5/6 Nx rats as compared with sham-operated controls. The increment, expressed as the left kidney weight/body weight, was significant higher in the HAD-fed rats than in SRD-fed animals. Glomerular volume also increased with time in the remnant kidney and the increment was higher in HAD-treated animals than in SRD-treated rats. In contrast, LAD-fed rats showed significant lower weight of the remnant kidney at week 13 and decreased glomerular volume from week 9 as compared with SRD-fed animals.Table 3Body weight, left kidney weight/body weight, and glomerular volumeWeek 5Week 9Week 13BW (g) HAD-fed 5/6 Nx rat319.1±16.3374.1±18.4422.2±20.5 LAD-fed 5/6 Nx rat324.1±13.6364.9±14.3420.5±8.9 SRD-fed 5/6 Nx rat320.6±17.4376.7±26.7416.7±15.3 Sham-operated control326.1±23.9368.8±11.7418.3±12.4KW/BW (g/kg) HAD-fed 5/6 Nx rat4.1±0.1aP<0.05, compared with SRD-fed 5/6 Nx rat.4.6±0.1aP<0.05, compared with SRD-fed 5/6 Nx rat.4.8±0.1aP<0.05, compared with SRD-fed 5/6 Nx rat. LAD-fed 5/6 Nx rat3.6±0.23.6±0.13.7±0.1aP<0.05, compared with SRD-fed 5/6 Nx rat. SRD-fed 5/6 Nx rat3.7±0.43.8±0.1bP<0.05, compared with Sham-operated control.4.2±0.1bP<0.05, compared with Sham-operated control. Sham-operated control3.6±0.23.1±0.13.2±0.1Glomerular volume (× 106μm3) HAD-fed 5/6 Nx rat1.84±0.012.31±0.05aP<0.05, compared with SRD-fed 5/6 Nx rat.2.54±0.07aP<0.05, compared with SRD-fed 5/6 Nx rat. LAD-fed 5/6 Nx rat1.62±0.051.70±0.14aP<0.05, compared with SRD-fed 5/6 Nx rat.1.96±0.08aP<0.05, compared with SRD-fed 5/6 Nx rat. SRD-fed 5/6 Nx rat1.69±0.052.0±0.06bP<0.05, compared with Sham-operated control.2.17±0.04bP<0.05, compared with Sham-operated control. Sham-operated control1.02±0.021.06±0.021.06±0.03BW, body weight; HAD, high-advanced glycation end products diet; KW, kidney weight; LAD, low-advanced glycation end products diet; Nx, nephrectomy; SRD, standard rodent diet.Data are expressed as mean±s.d.a P<0.05, compared with SRD-fed 5/6 Nx rat.b P<0.05, compared with Sham-operated control. Open table in a new tab BW, body weight; HAD, high-advanced glycation end products diet; KW, kidney weight; LAD, low-advanced glycation end products diet; Nx, nephrectomy; SRD, standard rodent diet. Data are expressed as mean±s.d. Glomerulosclerosis and interstitial fibrosis progressed with time in 5/6 Nx rats (Figure 2). Compared with SRD-fed rats, HAD-fed animals showed marked increase of glomerulosclerosis index (Figure 2a) and interstitial fibrosis score (Figure 2b) from week 5. Animals given LAD showed significant improvement of glomerulosclerosis and interstitial fibrosis in the remnant kidney as compared with rats received SRD. There was a close correlation between serum AGEs levels and glomerulosclerosis index (r=0.601, P<0.001, n=90) or interstitial fibrosis score (r=0.696, P<0.001, n=90) in 5/6 Nx rats (Figure 3a and b).Figure 3Relationship between serum AGEs levels and glomerulosclerosis index (a), interstitial fibrosis index (b), and macrophage infiltration in glomeruli (c) and in interstitium (d).View Large Image Figure ViewerDownload (PPT) To determine the glomerulotubular neck sclerosis, 72±44 glomeruli were studied per slide. About 6.9–29.5% of the glomeruli had identifiable glomerulotubular junctions. The average internal glomerulotubular junction lumen diameter was 24.0±7.5 μm in sham-operated controls, 8.8±3.6 μm in 5/6 Nx rats fed with HAD, 10.7±4.0 μm in SRD, and 18.7±6.7 μm in rats treated with LAD (analysis of variance (ANOVA), P<0.001; LAD vs HAD, P<0.001; LAD vs SRD, P<0.001). There were few ED1-positive cells in normal renal tissue removed at the time of the surgery and in sham-operated animals. Macrophage infiltration was evident in both glomeruli and interstitium of the remnant kidney. From week 5, the number of infiltrated macrophages was markedly increased in HAD- vs SRD-fed 5/6 Nx rats. Restriction of dietary AGEs significantly decreased macrophage infiltration in the remnant kidney (Figure 2c and d). A close correlation was found between serum AGEs levels and the number of ED1-positive cells in both glomeruli (r=0.728, P<0.001, n=90) and in interstitium (r=0.723, P<0.001, n=90) in the remnant kidney (Figure 3c and d). Subtotal nephrectomy resulted in renal dysfunction, as evidenced by progressive increase in serum creatinine (Figure 4a) and decline of creatinine clearance (Ccr) (Figure 4c). Systolic blood pressure (BP) did not change during the first 5 weeks, but progressively rose at latter time points (Figure 4d). HAD in 5/6 Nx rats significantly worsen renal dysfunction and proteinuria without altering systolic BP. In contrast, LAD-treatment significantly retarded renal dysfunction and decreased proteinuria at week 13 (Figure 4a–d). There was a close correlation between serum AGEs levels and urinary protein excretion (r=0.724, P<0.001, n=90) (Figure 4e) or Ccr (r=-0.342, P=0.001, n=90) (Figure 4f) in the 5/6 Nx rats. Immunohistological studies revealed that monocyte chemoattactant protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1) staining was limited to minimal positive reaction of tubular cells and negative in glomeruli. Among 5/6 Nx rats, positive staining of MCP-1 (Figure 5) and TGF-β1 (Figure 6) was observed in both tubulointerstitium and glomeruli. Compared with SRD-fed 5/6 Nx rats, higher staining scores were observed in HAD-fed rats and lower scores were found in LAD-fed animals (Figures 5a and b and 6a and b). Likewise, expression of MCP-1 (Figure 5c) and TGF-β1 mRNA (Figure 6c) were upregulated in HAD-fed rats and downregulated in LAD-fed 5/6 Nx rats as compared with SRD-fed animals.Figure 6Glomerular α-TGF-β1 staining score (a), tubulointerstitial α-TGF-β1 staining score (b), TGF-β1 mRNA expression (c), and urinary TGF-β1 levels (d) of 5/6 Nx rats on HAD (□), LAD (▨), SRD (▩), and control rats on SRD (▪). Data are expressed as mean±s.d., n=10 in each group at each time point. (a) ANOVA, P<0.01, (b) ANOVA, P<0.001, (c) ANOVA, P<0.05, (d) ANOVA, P<0.01 at week 5, 9, and 13. *P<0.05 vs SRD; **P<0.001 vs SRD; #P<0.05 vs control.View Large Image Figure ViewerDownload (PPT) Uninary MCP-1 (Figure 5d) and TGF-β1 (Figure 6d) were markedly increased in 5/6 Nx rats as compared with sham-operated controls. HAD-fed rats showed higher levels of urinary MCP-1 and TGF-β1 excretion than rats fed with SRD. Restriction of dietary AGEs significantly decreased urinary MCP-1 and TGF-β1 levels from week 9 (Figures 5d and 6d). As shown in Figure 7, thiobarbituric acid reactive substance (TBARS) and advanced oxidation protein products (AOPPs) levels in renal cortical homogenates significantly increased in 5/6 Nx rats. HAD treatment significantly increased TBARS levels (Figure 7a) and AOPPs levels (Figure 7b) from week 9. Glutathione peroxidase (GSHPx) activity decreased markedly in HAD-fed rats from week 9 as compared with SRD-fed animals (Figure 7c). At week 13, TBARS and GSHPx activity tended to restore in SRD-fed 5/6 Nx rats, but sustained in HAD-fed animals. LAD-treatment significantly decreased renal TBARS and AOPPs levels and increased GSHPx activity (Figure 7a–c). There was a close correlation between renal AGEs levels and renal TBARS (r=0.654, P<0.001, n=90) (Figure 7d), renal AOPPs (r=0.815, P<0.001, n=90) (Figure 7e), or renal GSHPx (r=-0.677, P<0.001, n=90) (Figure 7f). This study demonstrated that prolonged intake of food rich in AGEs in the remnant kidney model resulted in accelerated progression of renal damage and that certain aspect of this pathology were largely prevented by the restriction of dietary AGEs intake. Such restriction improves renal function, as evidenced by reduction of proteinuria and decrease of tubular fibrosis and glomerulosclerosis. It also retarded decline of renal function without alteration of BP. Although there is extensive evidence from both animals and clinical studies showing significant changes in circulating AGEs levels as a result of dietary AGEs modulation,8.Hofmann S.M. Dong H.J. Li Z. et al.Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse.Diabetes. 2002; 51: 2082-2089Crossref PubMed Scopus (248) Google Scholar, 9.Uribarri J. Peppa M. Cai W. et al.Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients.J Am Soc Nephrol. 2003; 14: 728-731Crossref PubMed Scopus (273) Google Scholar, 17.Šebeková K. Faist V. Hofmann T. et al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model.Am J Kidney Dis. 2003; 41: S48-S51Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 20.Cai W. Cao Q.D. Zhu L. et al.Oxidative stress-induced carbonyl compounds from common foods: novel mediators of cellular dysfunction.Mol Med. 2002; 8: 337-346PubMed Google Scholar to the best of our knowledge, this is the first study demonstrating that restriction of dietary AGEs intake in chronic renal insufficiency provides renal protection not only on proteinuria, but also on progression of renal fibrosis and dysfunction. Consistent with the previous reports,9.Uribarri J. Peppa M. Cai W. et al.Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients.J Am Soc Nephrol. 2003; 14: 728-731Crossref PubMed Scopus (273) Google Scholar,17.Šebeková K. Faist V. Hofmann T. et al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model.Am J Kidney Dis. 2003; 41: S48-S51Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar our results showed significant increase of serum CML immunoreactivity in 5/6 Nx rats fed with HAD. CML has been recognized as marker of glycoxidant burden in vivo19.Fu M.X. Requena J.R. Jenkins A.J. et al.The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions.J Biol Chem. 1996; 271: 9982-9986Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar,21.Singh R. Barden A. Mori T. Beilin L. Advanced glycation end-products: a review.Diabetologia. 2001; 44: 129-146Crossref PubMed Scopus (1767) Google Scholar and is thought to contribute to intracellular oxidative stress and tissue damage.19.Fu M.X. Requena J.R. Jenkins A.J. et al.The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions.J Biol Chem. 1996; 271: 9982-9986Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar However, the mechanisms by which dietary glycoxidation products increase serum CML remain to be investigated, as some studies report that CML may not be actively absorbed.22.Dittrich R. Hoffmann I. Stahl P. et al.Concentrations of Nepsilon-carboxymethyllysine in human breast milk, infant formulas, and urine of infants.J Agric Food Chem. 2006; 54: 6924-6928Crossref PubMed Scopus (57) Google Scholar,23.Grunwald S. Krause R. Bruch M. et al.Transepithelial flux of early and advanced glycation compounds across Caco-2 cell monolayers and their interaction with intestinal amino acid and peptide transport systems.Br J Nutr. 2006; 95: 1221-1228Crossref PubMed Scopus (57) Google Scholar Furthermore, we found that increased circulating AGEs were associated with enhanced burden of AGEs in renal tissue. Previous studies have demonstrated that approximately 10% of ingested AGEs enter the circulation, but only one-third are excreted within 3 days of ingestion.24.He C. Sabol J. Mitsuhashi T. Vlassara H. Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration.Diabetes. 1999; 48: 1308-1315Crossref PubMed Scopus (159) Google Scholar Chronic renal dysfunction or diabetes is associated with impairment in AGEs excretion.25.Howard B.V. Wylie-Rosett J. Sugar and cardiovascular disease: A statement for healthcare professionals from the Committee on Nutrition of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association.Circulation. 2002; 106: 523-527Crossref PubMed Scopus (129) Google Scholar Thus, dietary AGEs intake might be an important contributor to the body AGEs burden, particularly in renal insufficiency and diabetes. The increase in kidney-associated AGEs noted in HAD-fed rats can be attributed in large part to the covalent attachment of the exogenous AGEs onto to renal tissue through reactive moieties such as collagen or to the deposition of filtrated degradation products of AGEs proteins.13.Vlassara H. Striker L.J. Teichberg S. et al.Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats.Proc Natl Acad Sci USA. 1994; 91: 11704-11708Crossref PubMed Scopus (413) Google Scholar Renal function, as determined by Ccr, significantly decreased after nephrectomy. However, Ccr decreased by 68% at week 13 in 5/6 Nx rats corresponding to 83% resection of renal mass, suggesting that compensatory glomerular hyperfiltration occurred in this model. Supporting this notion, glomerular volume in 5/6 Nx rats significantly increased after renal mass reduction. The glomerular volume in the remnant kidney was higher in HAD-fed than SRD-fed rats. In contrast to the other report,17.Šebeková K. Faist V. Hofmann T. et al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model.Am J Kidney Dis. 2003; 41: S48-S51Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar it was not accompanied by any significant increase in body weight. Likewise, the protective effects of LAD were also marked against the glomerular hypertrophy, indicating that dietary intake of AGEs might be involved in the pathogenesis of renal mass hypertrophy and remodeling. It is interesting to note that LAD rats had less extent of glomeruli hypertrophy and more preserved Ccr. This might be related to the significant improvement of interstitial fibrosis in LAD as compared with HAD or SRD. It has been well established that interstitial fibrosis is a better predictor for renal impairment than glomerular changes.26.Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Abstract Full Text PDF PubMed Scopus (806) Google Scholar Sclerosis in the glomerulo-tubular neck, which is associated with interstitial fibrosis, provides an anatomic and functional link between tubulointerstitial fibrosis and loss of glomerular function.27.Cohen E.P. Robbins M.E. Whitehouse E. Hopewell J.W. Stenosis of the tubular neck: a possible mechanism for progressive renal failure.J Lab Clin Med. 1997; 129: 567-573Abstract Full Text PDF PubMed Scopus (18) Google Scholar The less sclerosis of glomerulo-tubular neck seen in LAD fed rats might decrease resistance to tubular flow, and contribute to more preserved glomerular filtration rate. Our results showed that modulation of diet AGEs content affected renal mass remodeling associated with renal mass reduction. The basic nutrients of the three diets and the daily food intake among the three groups of 5/6 Nx rats were comparable, and, there was no significant difference in serum albumin and lipid profile among groups during the study period, suggesting that the observed effects were not attributable to differences in nutrition or lipid profiles. AGEs can inhibit the activity of nitric oxide in previous study.28.Huang J.S. Chuang L.Y. Guh J.Y. et al.Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts.J Am Soc Nephrol. 2005; 1
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