Dietary Advanced Glycation End Products and Risk of Chronic Kidney Disease
Impact Factor: 2.929
Level of Evidence: VI
Type of Study and any information related to it: Longitudinal study. Follow-up surveys are given to patients every three years, including the Food Frequency Questionnaire.
Sample Size: 1,692 people over the age of 27 from Tehran, Iran recruited for a Lipid and Glucose Study based in dietary assessment
Important Methods: Consumption of carboxymethyl lysine (CML) was used as a proxy for dietary AGE intake. The daily CML intake was estimated using the FFQ. GFR was calculated through the Modification of Diet in REnal Disease Equation. Patients with an eGFR <60 mL/min/1.73m2 were considered to have CKD. eGFR=186×(Serum creatinine)−1.154×(Age)−0.203×(0.742iffemale)×(1.210ifAfrican−American)
Statistical Tests: A chi-squared test was used to analyze participant characteristics across AGE Intake Quartiles. Logistic regression was used to analyze AGE consumption and risk of CKD development. The regression model was adjusted for sodium intake, BMI, smoking, physical activity, energy intake, sex, and age.
Results: The average AGE intake was 8,336 kU/day (1,523 kU/day). The average incidence of CKD was 10.2% in the study population.
There was a significant relationship (P<0.001) with AGE consumption and percentage of fat intake. Additionally, as compared to participants in the first quartile of AGE intake from fat, participants in the fourth quartile of AGE intake from fat were at a 2.02 higher risk for developing CKD. There was no significant correlation between CKD incidence and AGE intake from meat.
Discussion: The vast majority (85.5%) of AGE intake in this study was obtained from fat and meat. AGE consumption was lowest in the patients with the highest total fiber consumption. Patients higher consumptions of dietary fats, had higher AGE consumptions, which was significantly related to increased CKD incidence.
Ejtahed HS, Angoorani P, Asghari G, Mirmiran P, Azizi F. Dietary Advanced Glycation End Products and Risk of Chronic Kidney Disease. J Ren Nutr. 2016 Sep;26(5):308-14. doi: 10.1053/j.jrn.2016.05.003. Epub 2016 Jun 30. PMID: 27373588.
Advanced glycation end products stimulate angiotensinogen production in renal proximal tubular cells.
Impact Factor: 1.911
Level of Evidence: III
Sample Size/Population: 11 mice (6 controls, 5 streptozotocin-induced DM mice)
Introduction: The augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC) plays a role in the development of diabetic nephropathy. This study investigated the hypothesis that AGE stimulates AGT production in PTC.
Protocol: Rat PTC was treated with 0-200 μg/ml AGE-BSA for 24 hours and cultured before AGT expression and secretion were evaluated. An ELISA assay was used to measure urinary AGT and AGE levels in streptozotocin-induced diabetes mellitus (DM) mice. qRT-PCR was used to evaluate AGT mRNA expression. Western blot analysis evaluated AGT levels, phosphorylation levels of p47phox, and activities of signal transducers and transcription factors. The expression of RAGE protein in PTC was confirmed by immunostaining.
Statistical analysis: Data was expressed as means ± standard error. Student t-test, 1-way ANOVA, post hoc Bonferroni/Dunn multiple comparison test. P <0.05 was considered statistically significant.
Type of Study: Mouse study.
Limitations: The sample size was relatively small at 11 mice in total.
Results: DM mice showed greeted urinary AGT and AGE levels compared to control mice. In cultured PCT, treatment with AGE-BSA enhanced AGT mRNA expression, intracellular AGT protein levels, and secreted AGT levels. AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK ½ and c-JUN, were observed in AGE-BSA treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor.
Discussion/Conclusions: AGE was found to enhance proximal tubular AGT expression via ERK ½ , which can exacerbate the development of diabetic related kidney injury. These findings provide a rationale for targeting AGE/RAGE pathway axis to suppress intrarenal RAS activity and prevent or treat kidney injury in DM.
Garagliano JM, Katsurada A, Miyata K, Derbenev AV, Zsombok A, Navar LG, Satou R. Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells. Am J Med Sci. 2019 Jan;357(1):57-66. doi: 10.1016/j.amjms.2018.10.008. Epub 2018 Oct 24. PMID: 30466736; PMCID: PMC6778966.
Restricted intake of dietary advanced glycation end products retards renal progression in the remnant kidney model.
Impact Factor: 8.945
Level of Evidence: VII
Sample Size/Population: 90 rats with ⅚ nephrectomy (⅔ removal of left kidney) divided into 3 groups of 30 rats each (standard rat diet, low AGE diet (LAD), and high AGE diet (HAD)), 30 control rats (sham surgery); Each of the 4 groups of 30 was further divided into groups of 10 rats which were harvested at 5, 9, or 13 weeks.
Protocol: ELISA and fluorospectrometry to measure concentration of AGEs in all specimens, histochemistry to determine extent of glomerular sclerosis, immunohistochemistry and RT-PCR to determine macrophage, TGF-β (involved in fibrosis) and MCP-1 (proinflammatory chemokine) levels and distribution in kidney tissue.
Statistical Analysis: A one-way ANOVA followed by Least Significant Difference method, independent sample t-test, Pearson correlation analysis, significance defined as P≤0.05.
Study type: Rat study.
Results: Serum AGE levels were significantly higher in rats with ⅚ nephrectomy compared to controls who had sham surgery. Rats in the HAD group had higher serum AGE levels than rats in the standard diet group, and rats in the LAD group had lower serum AGE levels than the standard diet group. The HAD group had increased weight of the remnant kidney and increased glomerular volume. The HAD group showed an increased glomerulosclerosis index and interstitial fibrosis score, while the LAD group had improved glomerulosclerosis and interstitial fibrosis. They found a close correlation between serum AGE levels and macrophages in glomeruli and interstitium of the kidneys. LAD rats had slowed renal dysfunction and decreased proteinuria, as well as decreased levels of MCP-1 and TGF-β in tubular cells and glomeruli. HAD rats had higher levels of renal oxidation reactions.
Discussion/Conclusion: In the setting of renal insufficiency, the consumption of AGEs by rats was associated with accelerated progression of renal damage, whereas a reduction of dietary AGE consumption slowed this progression. The increase in AGEs in the kidneys of HAD rats suggests that dietary AGE intake is an important contributor to the AGE burden particularly when there is impaired excretion of AGEs. The finding of less tubulointerstitial fibrosis in LAD rats may explain the more preserved glomerular filtration rate. This model showed that intrarenal oxidative stress and proinflammatory reactions can be largely inhibited by restricting dietary AGE consumption, potentially preventing the proposed positive feedback loop between AGE formation and oxidative stress.
Feng JX, Hou FF, Liang M, Wang GB, Zhang X, Li HY, Xie D, Tian JW, Liu ZQ. Restricted intake of dietary advanced glycation end products retards renal progression in the remnant kidney model. Kidney Int. 2007 May;71(9):901-11. doi: 10.1038/sj.ki.5002162. PMID: 17342181.
Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies.
Impact Factor: 4.731
Level of Evidence: I
Introduction: This review is an update of recent advances of diabetic nephropathy (DN), non-diabetic renal disease and renal aging.
Sample Size: N/A
Study Type: Review article
Summary: Chronic hyperglycemia promotes the formation of modified molecular species such as AGEs, which forms through glycation, the polyol pathway, and glycoxidation. AGEs are found in many renal structures, including atheromatous plaques within arteries. Their concentration in plaques correlates with the degree of atherosclerosis, seen even higher in diabetic patients with renal failure. Aside from DN, renal disorders including chronic renal failure, chronic inflammatory disease, high dietary AGE, and aging involve AGEs.
Further, AGE deposition is found in aterionephrosclerosis, IgA nephropathy, lupus nephritis, uraemia and the experimental murine model of focal sclerosis mediated by adriamycin. Still, it is uncertain to what extent kidney AGE accumulation is a cause or consequence of kidney disease, and AGEs could exert effects through a vicious cycle. Regarding renal ageing, it can be promoted through AGE accumulation, in situ glycation and RAGE activation. In terms of treatment, diet may play a key role in the prevention of AGE-linked pathologies. At this point, AGE inhibitors have been targeted for therapy including, aminoguanidine, 2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetalinide (OPB-9195), LR-90, LR-9, LR-74, pyridoxamine, and benfotiamine, with the most promising being the ‘LR’ inhibitors, pyridoxamine, and benfotiamine. Alagebrium (ALT-711), an AGE cross-link breaker, has also been studied for its role in limiting tissue AGE accumulation and reduction of AGE deleterious effects. ACE inhibitors, ARBs, statins, and some oral antidiabetics and antioxidative molecules are current treatments used for their ‘anti-AGE’ properties. The most promising therapies currently used for basic research include sRAGE and anti-RAGE antibody.
Daroux M, Prévost G, Maillard-Lefebvre H, Gaxatte C, D'Agati VD, Schmidt AM, Boulanger E. Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab. 2010 Feb;36(1):1-10. doi: 10.1016/j.diabet.2009.06.005. Epub 2009 Nov 22. PMID: 19932633.
The modern western diet rich in Advanced Glycation End-Products (AGEs): An overview of its impact on obesity and early progression of renal pathology.
Impact Factor: 4.546
Level of Evidence: II
Sample Size: N/A
Study Type: Review article
Statistical analysis: N/A
Results: AGE-induced kidney damage is a result of multiple interconnected factors which can lead to fibrotic damage in the ECM and sub-ECM components in the kidney. AGE’s are capable of increasing expression of monocyte chemoattractant protein-1 (MCP-1), particularly in the mesangial cells of the vascular region of the renal corpuscle. MCP-1 will recruit monocytes and macrophages which can lead to fibrotic changes in the kidney. Additionally, AGE’s can lead to TGF-b secretion through activation of RAGE which can lead to further fibrotic changes. As collagen is laid down in the ECM and sub-ECM, AGE is able to interact with type IV collagen to create proteoglycans which can increase permeability of the glomerulus, thus leading to the development of proteinuria and kidney disease.
As a part of the pro-inflammatory effects of AGE’s, the NF-KB pathway is upregulated which can lead to Zinc finger E-box binding homeobox 2 (ZEB2) gene upregulation in the kidney tissue. ZEB2 is known to decrease E-cadherin, P-cadherin, and nephrin expression in renal podocytes which can reduce podocyte count and damage the glomerulus.
Discussion: AGE’s lead to chronic inflammation in the kidney which can accelerate fibrotic processes and podocyte degeneration leading to chronic kidney disease. Additionally, AGE’s can play a role in the development of obesity, which can further chronic inflammation and impact renal health through separate pathways.
Bettiga A, Fiorio F, Di Marco F, Trevisani F, Romani A, Porrini E, Salonia A, Montorsi F, Vago R. The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): An Overview of Its Impact on Obesity and Early Progression of Renal Pathology. Nutrients. 2019 Jul 30;11(8):1748. doi: 10.3390/nu11081748. PMID: 31366015; PMCID: PMC6724323.
Uremic toxicity of advanced glycation end products in CKD.
Impact Factor: 9.274
Level of Evidence: V
Sample Size: N/A
Study Type: Review article
Statistical Analysis: N/A
Results: AGEs have been shown to accumulate as a result of inflammation, oxidative stress, and diet, and are themselves proinflammatory and pro-oxidative compounds. The accumulation of AGEs is involved in the cardiovascular complications seen in patients with Chronic Kidney Disease (CKD) through their contribution to endothelial dysfunction, arterial stiffness, myocardial changes, immune system dysregulation, and atherosclerosis. AGEs have also been shown to increase inflammation in patients with CKD by activating the NF-kB pathway which produces inflammatory cytokines. There are many potential strategies for therapeutic interventions to counteract the effects of AGEs, which include decreasing dietary intake, inhibiting gastrointestinal absorption, dialysis, kidney transplantation, agents that can break down AGEs, RAGE inhibitors, among others.
Discussion/Conclusion: AGEs can be high in chronic diseases with elevated levels of oxidative stress, such as CKD. Additional studies are needed to determine the role of AGEs in vascular function and the immune system in patients CKD, as well as what therapeutics could be used to decrease their detrimental effects.
Stinghen AE, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic Toxicity of Advanced Glycation End Products in CKD. J Am Soc Nephrol. 2016 Feb;27(2):354-70. doi: 10.1681/ASN.2014101047. Epub 2015 Aug 26. PMID: 26311460; PMCID: PMC4731113.
Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions.
Impact factor: 7.238
Level of evidence: VII
Sample size: n=3 for 3 month old mice, n=10 for 20 month old mice.
Protocol: They used histologic markers of aging (immunohistochemistry followed by HPLC/MS) in wild-type (WT) mice and RAGE knockout mice (RAGE-/-) over 18 months, on a diet rich in AGEs (CML) and a control diet; RT-qPCR and Western blot to measure gene/protein expression associated with kidney injury
Statistical Analysis: Kruskal-Wallis test followed by a Dunn’s multiple comparison test for multiple comparisons, two-tailed T-Test for samples with n=10, Mann-Whitney test for smaller samples (for both: P<0.05 was considered significant).
Study Type: In vivo using a mouse model.
Results: Accumulation of AGEs (CML) in proximal tubular cells and along renal arteries was found in both WT and RAGE-/- mice fed the CML-enriched diet. RAGE-/- mice fed the control diet were found to have significantly less endothelial dysfunction, tubular atrophy, interstitial fibrosis, and amyloidosis-linked glomerulosclerosis than WT mice fed the control diet. Certain inflammatory and oxidation markers increased less as RAGE-/- mice aged compared to WT.
Discussion/Conclusion: This study demonstrates that the RAGE receptor may play a role in the aging of kidney cells, however AGE-enriched diet was not found to have a significant effect on AGE accumulation and renal injury, and AGE accumulation seemed to be RAGE-independent. It is important to note that the sample sizes used in this study are small, which may have exaggerated the significance of the differences between groups. Also, some of the histologic data was not quantified, it is presented in percentages as assessed by an anatomopathologist and nephrologist.
Teissier T, Quersin V, Gnemmi V, Daroux M, Howsam M, Delguste F, Lemoine C, Fradin C, Schmidt AM, Cauffiez C, Brousseau T, Glowacki F, Tessier FJ, Boulanger E, Frimat M. Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions. Aging Cell. 2019 Apr;18(2):e12850. doi: 10.1111/acel.12850. Epub 2019 Feb 22. PMID: 30794349; PMCID: PMC6413655.
Advanced glycation end products (AGE) and receptor for AGE (RAGE) in patients with active tuberculosis, and their relationship between food intake and nutritional status.
Impact Factor: 3.673
Sample Size/Population: 35 tuberculosis (TB) patients and 35 controls. Patients and controls were individually matched for sex and age in a 1:1 matching ratio.
Protocol: TB patients selected from the hospital and members of the control group (healthy volunteers selected from the TB patients family to account for same daily exposures) were interviewed using a standardized questionnaire. Subjects then completed a series of diagnostic tests including: blood samples to test CML and sRAGE levels, chest x-rays evaluated by an independent physician for evidence of active TB, and a nutritional assessment. The outcome of hospitalization (discharge or death) was also recorded.
Statistical Analysis: Shapiro-Wilk test for normality, chi-square test for categorical comparisons, paired t-test or Wilcoxon test for continuous variables, Pearson’s correlations used to evaluate potential relationships. Considering a confidence level of 95% and a power of 80%, sample size was calculated based on the expected difference of sRAGE levels between survivors and non-survivors and estimated to be a sample of 30 individuals per group.
Study Type: Case-Control Study.
Results: The most common symptoms TB patients experienced according to the questionnaire were weight loss (94.3%), cough (88.6%), night sweats (65.7%), and fever (62.9%). Within the TB patient sample group: 40.0% were HIV positive, 80.0% were sputum smear TB positive, and 80.0% had a positive Mycobacterium tuberculosis complex culture. White race was more common in the control group as 82.9% of the control group were of white race, and 54.3% of the TB patients were of white race. 74.3% of TB the patients had a typical chest x-ray, and 80% of the sample group were survivors.
The mean sRAGE levels were higher in TB patients than the controls (68.5 ± 28.1 pg/mL vs 57.5 ± 24.0 pg/mL, p = 0.046). BMI was significantly lower in TB patients than in controls (p<0.0001). Malnutrition measured by MUAC, MAMC, and TSF were each more frequent in TB patients than in controls. There was no statistically significant difference in CML levels and diet CML content between TB patients and controls. There was no statistical significance between serum CML levels and diet CML levels, or between BMI and CML levels, or between BMI and sRAGE levels. Malnutrition measured by MUAC, MAMC, and TSF were also not correlated with CML or sRAGE levels. There was also no statistical significance between CML in diet content between TB patients and controls. No statistical difference was found in serum CML levels, diet CML content, or sRAGE levels between survivors and non-survivors. Among the individuals that were current smokers, lower levels of sRAGE were statistically associated with mortality (sRAGE levels [mean ± SD] = 58.0 ± 36.5 pg/mL [non-survivors] vs 71.3 ± 25.6 pg/mL [survivors], p = 0.006; odds ratio 1.053 [CI95% 1.006–1.103]). Lower sRAGE levels were associated with weight loss in TB patients (sRAGE levels [mean ± SD] = 65.6 ± 27.4 pg/mL [weight loss] vs 98.6 ± 16.7 pg/mL [no weight loss], p = 0.034).
Conclusion: The study found that sRAGE levels were higher in TB patients than in controls, however it is unclear if that difference is clinically relevant because sRAGE is a competitive inhibitor of RAGE. One possible hypothesis is that the enhanced RAGE expression and cellular damage that comes with disease increases sRAGE generation and release. In that instance sRAGE could be used to measure RAGE hyperactivity. There was no statistical evidence of a difference between TB patients and control CML levels. The authors suspect that this could be due to the fact that the sample size was limited and the fact that RAGE is capable of binding multiple ligands other than AGEs. Contrastingly, lower sRAGE levels were associated with weight loss and mortality among the individuals who were current smokers.
da Silva LF, Skupien EC, Lazzari TK, Holler SR, de Almeida EGC, Zampieri LR, Coutinho SE, Andrades M, Silva DR. Advanced glycation end products (AGE) and receptor for AGE (RAGE) in patients with active tuberculosis, and their relationship between food intake and nutritional status. PLoS One. 2019 Mar 14;14(3):e0213991. doi: 10.1371/journal.pone.0213991. PMID: 30870511; PMCID: PMC6417785.
Clinical studies of advanced glycation end product inhibitors and diabetic kidney disease.
Impact Factor: 3.686
Level of Evidence: II
Type of Study: Review article.
Results: The study discusses the clinical trial results of 3 AGE inhibitors. In a phase 3 clinical trial, Pimagedine (a competitive inhibitor of the AGE pathway) was not found to be more efficacious than placebo in reducing serum creatinine in patients with type I diabetes, but it did reduce urinary protein excretion and lipid levels. However, the study was suspended due to adverse events, particularly the development of crescentic glomerulonephritis in several participants. Pyridoxamine, a vitamin B6 derivative that has been shown to inhibit AGE formation in animal models, had promising results in a phase 2 trial and is awaiting a phase 3 trial. Its proposed mechanisms of AGE formation inhibition include carbonyl trapping and scavenging of metal ions in vivo, and it can inhibit the degradation of protein-Amadori products into AGEs. Alagebrium is a cross-link breaker, and thus an AGE inhibitor since AGEs mediate protein cross-linking. Current clinical trials with this drug are focused on its potential for reducing vascular stiffness caused by increased collagen cross-links, but it may also have effects on the increased collagen cross-links associated with diabetes and needs to be studied further. Another pharmacological target for reducing diabetic kidney disease is glycated albumin, which may be inhibited in a similar way to AGE inhibition.
Discussion/Conclusion: There are several AGE inhibitors currently in different stages of development and clinical trials. Further research is needed to find pharmacological agents that can reduce the impact of AGE formation on diabetic nephropathy and other pathology associated with AGEs.
Williams ME. Clinical studies of advanced glycation end product inhibitors and diabetic kidney disease. Curr Diab Rep. 2004 Dec;4(6):441-6. doi: 10.1007/s11892-004-0054-0. PMID: 15539009.
Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products.
Impact Factor: 6.628
Level of Evidence: III
Sample Size: 51
Protocol: Cross-sectional study of ambulatory patients without diabetes and with different stages of CKD (compared with gender- and age-matched healthy subjects).
Statistical Analysis: The Kolmogorov-Smirnov goodness-of-fit test.
Type of Study: Cross-sectional study.
Results: There was a correlation between glomerular filtration rate and serum AGEs, mRNA receptor for AGE levels, postocclusive reactive hyperemia, and thermal hyperemia. Serum AGE product was correlated with the receptor for AGEs and was inversely correlated with postocclusive reactive hyperemia. Serums from chronic kidney disease that were rich with AGE were found to suppress endothelial nitric oxide synthase expression of human aortic endothelial cells when compared to serums of healthy subjects.
Discussion/Conclusion: Excess AGE product burden with increased peripheral blood mononuclear cell mRNA receptor for advanced glycation end product and in vivo endothelial dysfunction in patients with chronic kidney disease. Endothelial dysfunction in chronic kidney disease may be, in part, mediated by AGE product–induced inhibition of endothelial nitric oxide synthase through receptor for advanced glycation end product activation.
Linden E, Cai W, He JC, Xue C, Li Z, Winston J, Vlassara H, Uribarri J. Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation. Clin J Am Soc Nephrol. 2008 May;3(3):691-8. doi: 10.2215/CJN.04291007. Epub 2008 Feb 6. PMID: 18256374; PMCID: PMC2386710.
Advanced glycation end products predict loss of renal function and correlate with lesions of diabetic kdney disease in American Indians With type 2 diabetes.
Sample size: 168 American-Indian participants with type II diabetes
Protocol: During a 6 year clinical trial used to determine the efficacy of the drug Losartan, GFR was measured annually and a kidney biopsy was performed at the beginning and end of the trial. Five different AGEs were measured in serum at the beginning of the trial. Renal function loss (RFL) was determined to be a decline of 40% or more from baseline GFR.
Statistical Analysis: Pearson’s correlation, Cox proportional hazard regression
Study Type: Randomized control trial
Results: AGE concentration was associated with RFL and positively correlated with cortical interstitial fractional volume. AGEs were also negatively correlated with total filtration surface per glomerulus.
Conclusion: AGEs may be used to predict RFL in diabetics, since the kidneys are unable to clear the AGEs. The number of AGEs is also associated with a specific renal lesion which may contribute further to the loss of renal function.
Saulnier PJ, Wheelock KM, Howell S, Weil EJ, Tanamas SK, Knowler WC, Lemley KV, Mauer M, Yee B, Nelson RG, Beisswenger PJ. Advanced Glycation End Products Predict Loss of Renal Function and Correlate With Lesions of Diabetic Kidney Disease in American Indians With Type 2 Diabetes. Diabetes. 2016 Dec;65(12):3744-3753. doi: 10.2337/db16-0310. Epub 2016 Sep 8. PMID: 27609106; PMCID: PMC5127241.
Pathophysiology and therapeutics of premature ageing in chronic kidney disease, with a focus on glycative stress.
Impact Factor: 2.456
Level of Evidence: V
Study Type: Review article
Results: High levels of FGF23 and angiotensin II are frequently detected in CKD patients. These high levels can accelerate aging directly or through hyperphosphatemia and hypertension. Renal hypoxia, which can be induced by renal hypoxia, can increase glycative stress due to increased oxidative stress. Many factors are involved in premature ageing in CKD, including hormonal imbalance, glycative stress, nitrogenous metabolites, and oxidative stress. Of these, the most important role in premature ageing in CKD is played by glycative stress, namely a massive and unfavourable glycation state, since the kidney is responsible for the clearance of advanced glycation endproducts (AGEs).
Discussion/Conclusion: Factors such as FGF23, angiotensin II and indoxyl sulphate are often found at high levels in patients with CKD, which can accelerate premature aging in the patient. Interventions that target the glycative stress caused by these factors, such as enforcing overexpression of glyoxalase (GLO-1) can detoxify advanced glycation endproducts (AGEs) and can help alleviate premature aging in the kidneys. These strategies can only be carried out when there is a greater understanding of what is needed in the field. Clinical trials focused on the anti-aging effect of drugs can also lead to further research and studies in this field.
Hirakawa Y, Jao TM, Inagi R. Pathophysiology and therapeutics of premature ageing in chronic kidney disease, with a focus on glycative stress. Clin Exp Pharmacol Physiol. 2017 Dec;44 Suppl 1:70-77. doi: 10.1111/1440-1681.12777. Epub 2017 Sep 20. PMID: 28467603.
Advanced glycation end products in the pathogenesis of chronic kidney disease.
Impact Factor: 8.395
Level of Evidence: II
Type of Study and any information related to it: Review
Important Methods: No search criteria listed
Results: A specific AGE precursor, methylglyoxal (MG), has been linked to the development of CKD. MG is metabolized by the glyoxalase system in the kidney. Patients with decreased expression of Glyoxalase 1 expression may be at higher risk for renal impairment from AGE accumulation. This is highlighted by the use of pharmaceutical glyoxalase 1 inducers to limit the extent of nephropathy. As CKD develops, AGE’s can accumulate in the body and cause other health effects. AGE free adducts are the main way AGE’s are excreted from the body. In patients on hemodialysis and peritoneal dialysis, there have been reported 4 to 40 times increases in AGE free adducts.
Discussion: Methylglyoxal accumulation is a mediator of AGE-related kidney damage. The use of glyoxalase 1 inducers to improve methylglyoxal clearance has been shown to limit renal damage.
Rabbani N, Thornalley PJ. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int. 2018 Apr;93(4):803-813. doi: 10.1016/j.kint.2017.11.034. Epub 2018 Feb 22. PMID: 29477239.
Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1.
Impact Factor: 3.703
Level of Evidence: VII
Type of study and any information related to it: in vivo studies with rats and in vitro studies using rat mesangial cells
Sample size: 5 groups of 6 rats
Important methods: PAS staining and immunohistochemistry for observing renal changes, Western blot and RT-PCR to measure protein and RNA levels, respectively, of PAI-1 and PPAR-𝛾, ELISA to measure fibronectin, Col IV, and PAI-1 in mesangial cells, plasminogen gel zymography and activity assays to detect renal plasminogen activator activity
Statistical tests ran: t-Test, one-way ANOVA, (p <0.05 considered to be significant)
Results: All animals that were treated with AGEs had mild renal dysfunction, determined by increase in urinary protein excretion. The animals that were given Rosiglitazone (RGZ) or an AGE cross-link breaker (AG) in addition to AGEs had significantly less renal dysfunction and less ultrastructural abnormalities in glomerulus. Treatment with RGZ or AG also significantly reduced the amount of fibronectin and Col IV in the glomerulus. PAI-1 RNA and protein were found to be significantly increased in animals given AGEs, resulting in decreased plasminogen activator activity. These levels were nearly normal in animals that were also given RGZ or AG. Similarly, PPAR-𝛾 mRNA and protein levels were decreased in the AGE group of animals, but almost normal in RGZ and AG groups. Through in vitro studies, it was found that AGEs increase PAI-1 expression and significantly decrease plasminogen activator activity and increase in fibronectin and Col IV levels. Coaddition of RGZ prevented these effects. Also, cells treated with PAI-1 antibody prior to exposure to AGEs had almost no AGE-induced fibronectin and Col IV production.
Discussion/Conclusion: Overall, the results of this study suggest that AGEs are involved in the accumulation of extracellular matrix, at least in part through the upregulation of PAI-1. AGEs were also linked to decreased PPAR-𝛾 expression, and they found that treatment with Rosiglitazone, a PPAR-𝛾 agonist, can largely prevent the effects of AGEs by suppressing PAI-1. Rosiglitazone had similar effects to the AGE formation inhibitor (AG) in terms of preventing extracellular matrix accumulation and renal dysfunction. The sample sizes were small, but this study used both in vivo and in vitro experiments and tested many different aspects of this pathway leading to renal dysfunction. It is still unclear how the addition of AGEs causes upregulation of PAI-1, something that would warrant further study.
Yu X, Li C, Li X, Cai L. Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1. Toxicol Sci. 2007 Apr;96(2):346-56. doi: 10.1093/toxsci/kfm010. Epub 2007 Jan 29. PMID: 17264099.
Dietary advanced glycation end products and aging.
Impact factor: 4.546
Level of evidence: Level I
Type of study and any information related to it: This is a review article that discusses the results of several studies that used human and animal models to show that restricting dietary advanced glycation end products (AGEs) has a positive impact on wound healing, insulin resistance and cardiovascular disease and could potentially increase lifespan. The article also explores the various implications that AGEs have on human health and some limitations in the current body of research on AGEs.
Discussion/Conclusion: AGEs are a diverse group of compounds formed through the Maillard reaction. The final AGE product is ultimately formed through a set of oxidation, reduction, and hydration reactions that result in irreversibly crosslinked proteins. Additionally, the polyol pathway (Lipid peroxidation) and glucose autoxidation can lead to the formation of AGEs, contributing to the diversity in their chemical structure. Many AGEs have fluorescent properties that are frequently measured to assess their levels in studies. AGEs accumulate inside and outside of cells and can lead to proinflammatory and pro-oxidant effects in tissues through receptor independent mechanisms and by interacting with the receptor for advanced glycation end products (RAGE). AGE interaction with RAGE leads to the activation of mitogen activated protein kinases (MAPKs) and phosphatidylinositol-3 kinase (PI3-K) pathways that both lead to the activation of NF-kB (nuclear factor kappa B). These pathways increase the production of proinflammatory factors such as tumor necrosis factor α (TNFα), interleukin 6 (Il-6), and vascular cell adhesion molecule 1 (VCAM 1). Additionally, NF-kB increases RAGE expression which creates a positive feedback cycle that promotes inflammation. RAGE activation also increases intracellular oxidative stress through the activation of NADPH oxidase which further stimulates the activation of NF-kB. Research has suggested that the pro-oxidant and inflammatory properties of AGEs are a risk factor for Alzheimer’s disease with one study finding higher levels of AGEs and RAGE expression in the brain tissue of Alzheimer’s disease patients when compared to brain tissue from normal patients.
The accumulation of AGEs impacts various chronic and neurological diseases such as cardiovascular disease, sarcopenia, renal disease, diabetes and many others. Several studies have found that AGEs are contributing to cardiovascular disease through several mechanisms. One paper described how AGEs can promote the stiffening of blood vessels. Another study showed that AGE accumulation can lead to glycation of low-density lipoprotein (LPL) particles that increase the risk for atherosclerosis.
Research has also suggested that AGE accumulation can decrease the level of nitric oxide (NO) in the body, an important vasodilator that helps prevent atherosclerosis. Research has found a relationship between the buildup of AGEs and the development of sarcopenia. Studies found that AGEs could contribute to a decline in muscular function in older populations by increasing oxidative stress and inflammation. Specifically, one study found that higher levels of the circulating AGE carboxymethyl-lysine (CML) was associated with decreased grip strength in older women. Further research is needed to conclude a causal relationship between AGEs and sarcopenia.
The relationship between AGEs and renal disease has been studied primarily in patients with type 2 diabetes. Two studies have found an association between CML and a decrease in glomerular filtration rate in older men and women. While more research is needed, these studies suggest there could be a relationship between high levels of CML and decreased renal function.
AGEs can be made in vivo and found in various products such as food and cigarettes. It is believed that the processing of tobacco leaves can increase the accumulation of AGEs inside of the human body. Cerami et al has suggested that glycotoxins found in cigarettes are transported into circulation or lung cells and from there they can contribute with AGE formation. The Western diet has been found to be a large source of exogenous AGEs. Treating food with heat, a norm in our society used to enhance the taste, color, and smell of food, has been found to promote the Maillard reaction and can increase the rate at which we accumulate AGEs inside our body. Industrial products, such as soda, often have products of the Maillard reaction added to them. Using an AGE specific enzyme-linked immunosorbent assay (ELISA) it was found that ~10% of ingested immunoreactive AGEs are transported into circulation and that two thirds of them stay in the body while one third of them are excreted through the kidneys. Melanoidins are a subset of AGE products found in coffee, bakery products and bread crust. Interestingly, research has shown that melanodins can have a potentially positive effect on human health by promoting the growth of beneficial bacteria in the digestive system and improving the activity of liver enzymes.
While the mechanism for the absorption of AGEs is still an active area of research, one study has found that the absorption of one AGE product, pyrraline, is through the peptide transporter hPEPT1. Another study found that subjects had increased urinary output of AGE products (pyrraline and pentosidine) for three days after being given specific amounts of custard, pretzels or brewed coffee. The metabolic and absorptive pathways for various AGEs are largely unknown and more work is needed on these topics.
AGE homeostasis is balanced between the consumption of AGE products, endogenous production, renal excretion and enzymatic detoxification. Enzymes such as glyoxalase I, II and carbonyl reductase and the receptor AGER1 play a role in the detoxification of AGEs. Research suggests that an increase in endogenous production and a decrease in renal excretion can increase the rate at which AGEs accumulate in the older population. A study investigated the glycotoxin levels, a measure of oxidative stress, in an older (60 to 80 years of age) and younger (18 to 45 years of age) group of volunteers. The markers for AGEs were higher in the older group and were found to be correlated with oxidative stress. Researchers hypothesized that AGE accumulation in tissues might lead to increased oxidative stress which ultimately leads to a decline in tissue and organ function. It is possible that decreased renal function in older adults is contributing to higher AGE levels in that population.
Several strategies have been proposed to help reduce AGE levels through dietary, exercise and pharmacological means. One way to reduce AGEs is by decreasing the heat used to prepare food. Studies have found that reducing AGEs in humans can help reduce inflammatory factors such as TNF-α and high sensitivity C-reactive protein (hsCRP) and even decrease insulin resistance in diabetic mice. Studies demonstrated in C. elegans and mice models that a reduced caloric intake can lead to an increased lifespan. Researchers suggested the benefit to a reduced caloric intake was because of a decrease in the intake of AGEs which subsequently reduce the level of oxidative stress.
There have been few studies on the relationship between exercise and AGE accumulation. One study found that exercise trained diabetic rats had lower levels of AGEs compared to sedentary diabetic rats. Another study found exercise training decreased age-related decline in cardiac contractility and myocardial stiffness in older rats compared to controls. It was hypothesized that exercise training can decrease AGE related cross linking in myocardial tissue which leads to increased cardiac performance. A studying using healthy Malaysian adults found that practicing Tai Chi two times per week led to a decrease in the concentration of AGEs and a marker for lipid oxidation when compared to a sedentary control group. Another study had seventeen women (30 to 70 years of age) participate in a lifestyle modification protocol for three months during which the intervention group increased their physical activity. When compared to the control group, the intervention group had lower markers of AGEs.
Various pharmacological interventions have been studied in human and mice models such as benfotiamine, a B1-like vitamin with increased bioavailability, metformin, aminoguanidine, aspirin and inhibitors of the renin-angiotensin system. One study demonstrated that Candersatan, an angiotensin receptor antagonist, can help reduce CML levels in the urine of patients with diabetic kidney disease. Metformin has demonstrated the ability to reduce AGE levels in diabetic patients. Many of the pharmacologic agents are still in clinical trials and it may be a long time before any of them are deemed a safe and effective way to reduce AGEs.
Difficulties: Part of the issue studying AGEs is the heterogeneity of the different products that can be formed form the Maillard reaction. Only a handful of the products have been well characterized, with CML being one of the first AGEs characterized in food. The high diversity has made it difficult to study the impact AGEs have on human health. Additionally, some AGE products have fluorescent properties that allow them to be measure using chromatography while other AGEs have been measured using immunohistochemistry. It would be beneficial for future studies to have an agreed upon method to measure AGEs.
Another limitation in the current body of work on AGEs is that studies investigating the effect of reducing exogenous AGEs have been mainly in patients with renal disease or diabetes. More long-term studies with older individuals are needed to determine the effect AGEs have on human health and the true impact of reduction strategies.
Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients. 2010;2(12):1247-1265. doi:10.3390/nu2121247
Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis.
Level of Evidence: V
Type of Study: In Vivo
Detailed Summary: Systemic Lupus Erythematosus is a chronic disease with a prevalence of about 150 in every 100,000 people. It is an autoimmune condition that is characterized by a “butterfly rash”, hair loss, anemia, and joint swelling. It is considered to be multifactorial with people who are affected by the disease having other family members that are affected with autoimmune diseases and also trauma, stress, and environmental factors seemingly having a role in the condition. Both the presentation of systemic Lupus Erythematosus and Lupus Nephritis was studied to see if there was a connection between the two diseases and the receptor for advanced glycation products.
In the execution of this study, there were 97 patients with Lupus, 114 patients with lupus nephritis, and 429 people who were controlled and were not diagnosed with either disease. There were four advanced age glycation receptor polymorphisms that were measured in this disease. In the patients with Lupus, an ELISA test was used specifically in order to test for the polymorphisms. There were three polymorphisms that were significantly increased in those patients that had been suffering from Lupus. There were three more polymorphisms that were increased in those patients who were suffering from Lupus Nephritis and those patients had experienced more symptoms such as proteinuria. It is seen that there is an increase in polymorphisms that are increased in Lupus patients and Lupus Nephritis. This is indicative of making sure we continue to do so in other autoimmune diseases, so we may be steps closer to a cure where in many of these diseases a cure is not existent.
Martens, H. A., Nienhuis, H. L. A., Gross, S., van der Steege, G., Brouwer, E., Berden, J. H. M., de Sévaux, R. G. L., Derksen, R. H. W. M., Voskuyl, A. E., Berger, S. P., Navis, G. J., Nolte, I. M., Kallenberg, C. G. M., & Bijl, M. (2012). Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis. Lupus, 21(9), 959-68. https://doi.org/10.1177/0961203312444495
Serum levels of advanced glycation endproducts and other markers of protein damage in early diabetic nephropathy in type 1 diabetes.
Impact Factor: 2.740
Level of Evidence: III
Sample Size: 30 patients with longstanding normoalbuminuria and 55 patients with new onset microalbuminuria were followed up 8-12 years to determine GFR status.
Protocol: Glycation, oxidation and nitration markers were measured in protein and ultrafiltrate at baseline by liquid chromatography-tandem mass spectrometry using the most reliable methods currently available.
Statistical Analysis: Student's T-test for continuous variables and chi-squared for categorical variables. For urinary albumin excretion and the plasma free adduct concentrations, two-way comparisons were made in the log-scale using Wilcoxon rank sum tests and the trend across the three groups was made by Kruskal-Wallis.
Study Type: Prospective
Results: Patients with microalbuminuria had 8-12 years follow-up during which 33 had stable GFR and 22 early GFR decline. Though none were significantly different between patients with microalbuminuria with stable or early GFR decline, levels of 6 protein damage adduct residues of plasma protein and 4 related free adducts of plasma ultrafiltrate were significantly different in patients with microalbuminuria compared to normoalbuminuria controls.
Conclusion: Complex processes influence levels of plasma protein damage and related proteolysis produce free adducts in type 1 diabetes and microalbuminuria. The effects observed point to the possibility that patients who have mechanisms of disposal of damaged proteins might be at an increased risk of developing microalbuminuria but not early renal function decline.
Bruce A Perkins, Naila Rabbani, Andrew Weston, Linda H Ficociello, Antonysunil Adaikalakoteswari, Monika Niewczas, James Warram, Andrzej S Krolewski, Paul Thornalley DOI: 10.1371/journal.pone.0035655
Receptors for advanced glycation end products are associated with autophagy in the clear cell renal cell carcinoma.
Impact Factor: 1.326
Type of Study: In vitro
Sample Size: 12 RCC patients, who received tumor nephrectomy at first affiliated hospital of Wenzhou Medical University
Introduction: Renal cell carcinoma (RCC) is a common urologic cancer in which tumor microenvironment (TME) contributes to the progression of malignancy. The involvement of the receptor for advanced glycation end-product (RAGE) has been established in other cancers, but its contributions in renal cancer was unknown. High mobility group box 1 (HMGB1) is a nuclear DNA binding protein functioning as a potent proinflammatory cytokine, which also has roles in the pathogenesis of RCC and other kidney diseases. Since autophagy was suggested to be a key factor for regulating human cancer cell survival, the investigators suspected RAGE-mediated autophagy might play critical roles in TME. This study evaluated the relationship between HMGB1/RAGE and autophagy in clear cell RCC (ccRCC).
Methods: RCC tissues and paired adjacent non tumorous renal tissues (≥3 cm away from the tumor, confirming no cancer cell was found in tangent lines) were collected from 12 RCC patients, who received tumor nephrectomy at first affiliated hospital of Wenzhou Medical University. These samples were collected from January 2016 to July 2016. A western blot analysis, RNA extraction and quantitative reverse-transcription PCR (qRT-PCR), high-mobility group box 1 silencing and overexpression in the A498 and ACHN cell lines, and immunofluorescence was performed.
Statistical analysis: All data was expressed as mean values ± standard deviation. A paired Student’s t-test was used to assess differences between 2 groups. P <0.05 indicated statistical significance.
Results: The protein expression of HMGB1/RAGE, LC3, Beclin-1, and PI3K in ccRCC samples and adjacent normal tissues was analyzed to determine the relationship between HMGB1/RAGE expression and autophagy. mRNA expression of HMGB1/RAGE, LC3, Beclin-1, and PI3K was evaluated with qRT-PCR. Protein expression and mRNA expression of HMGB1, RAGE, LC3, Beclin-1, and PI3K in ccRCC samples was much higher than in the adjacent normal tissue. Immunofluorescence further confirmed the relationship of HMGB1/RAGE and autophagy with the previously stated results. qRT-PCR and immunofluorescence also was used to evaluate the interactions of HMGB1 and RAGE as well as HMGB1, RAGE, and LC3, respectively. With qRT-PCR, it was found that the knockdown of HMGB1 would down-regulate the mRNA expression of RAGE, and LC3 and Beclin-1 would be down-regulated as well. On the other hand, the overexpression of HMGB1 up-regulated RAGE as well as mRNA expression of LC# and Beclin-1. Immunofluorescence showed that overexpression of HMGB1 up-regulated LC3 and RAGE levels, in addition to decreased levels in the HMGB1-siRNA1 group. HMGB1-Vec+sRAGE group showed increased expression of LC3, while it was decreased compared to the sRAGE group. Therefore, these results suggested HMGB1 has an important role in RAGE and autophagic protein (LC3, Beclin-1, PI3K) expression in RCC cells.
Discussion/Conclusions: HMGB1 expression in the patients’ pathological samples confirmed that ccRCC was related to the PT1b classification and tumor grade. Methylation of HMGB1 at lysine 112 in ccRCC, affected its binding capacity with DNA, as well as translocation mediation. It was also found that HMGB1 promoted ccRCC development and progression through ERK1/2 activation, which is partially regulated by RAGE. The collective findings suggest that HMGB1 and RAGE could be potential targets for treatment of ccRCC. Limitations: Small sample size from a single hospital
Guo Y, Zhang HC, Xue S, Zheng JH. Receptors for advanced glycation end products are associated with autophagy in the clear cell renal cell carcinoma. J Cancer Res Ther. 2019;15(2):317-323. doi: 10.4103/jcrt.JCRT_180_18. PMID: 30964104.
Transforming Growth Factor-β1 and Receptor for Advanced Glycation end Products Gene Expression and Protein Levels in Adolescents with Type 1 Diabetes Mellitus.
Impact Factor: 1.803
Detailed Summary: A qPCR test was run on T1D’s (only receiving insulin therapy) and a control group. The qPCR test for the levels of TGF-B1 and full-length transmembrane receptors for AGE’s (flRAGE) messenger RNA levels on the peripheral blood mononuclear cells (PBMC). They also did a serum test for soluble RAGE (sRAGE) and the amount of TGF-B1. The results of this study showed that TGF-B1 and sRAGE levels were elevated in T1D patients. This indicates the downregulation of gene expression of flRAGE mRNA in PBMC of these patients. This decrease in TGF-B1 can be an indication of diabetic nephropathy, a complication of T1D. This study was conducted by an in-vivo case-control study. The TGF-B1 and flRAGE is statistically significant with a P value of .001 for both indicators being higher in the control population. In addition, the TGF-B1 and sRAGE both had statistically significant values of P= 0.001 with both of those being higher in Type 1 Diabetes Mellitus. The study contained 156 adolescents with T1D and 80 controls who were healthy.
Ninić A, Bojanin D, Sopić M, Mihajlović M, Munjas J, Milenković T, Stefanović A, Vekić J, Spasojević-Kalimanovska V. Transforming Growth Factor-β1 and Receptor for Advanced Glycation end Products Gene Expression and Protein Levels in Adolescents with Type 1 Diabetes Mellitus. J Clin Res Pediatr Endocrinol. 2020 Sep 17. doi: 10.4274/jcrpe.galenos.2020.2020.0155. Epub ahead of print. PMID: 32936764.
Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes
Impact Factor: 8.945
Summary: A cross-sectional study was done to determine the role of low molecular weight advanced glycation end products (LWM AGE’s) role in nephropathy in type 2 diabetic patients. The study followed 604 patients in a single clinic over a two-year period. They measured the LWM AGEs in the serum. The study found the LWM AGE’s were significantly higher in T2DM patients ( P 0.001) than non diabetics. The patients with renal disease and anemia had the highest level of LWM AGE’s. The study concluded that LMW AGE correlated (either a marker or a contributor) with the chance of renal injury and development of nephropathy in T2DM patients.
Thomas MC, Tsalamandris C, MacIsaac R, Medley T, Kingwell B, Cooper ME, Jerums G. Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes. Kidney Int. 2004 Sep;66(3):1167-72. doi: 10.1111/j.1523-1755.2004.00868.x. PMID: 15327413.
Lysozyme enhances renal excretion of advanced glycation endproducts in vivo and suppresses adverse age-mediated cellular effects in vitro: a potential AGE sequestration therapy for diabetic nephropathy?
Impact Factor: 10.61
Summary: A case study was done on non-obese diabetic (NOD) rats and non-diabetic advanced end glycation product infused mice. The aim of this study was to determine how effective lysozyme (LZ) was in prevention of diabetic complications. In the NOD mice the LZ reduced the amount of AGE’s (p value of 0.05). In the infused mice LZ also reduced the AGE’s (p value of 0.05). In addition, the LZ stimulated the uptake and degradation of AGE’s. This study was able to conclude that LZ is potentially helpful in the prevention of diabetic complications especially renal damage.
Zheng F, Cai W, Mitsuhashi T, Vlassara H. Lysozyme enhances renal excretion of advanced glycation endproducts in vivo and suppresses adverse age-mediated cellular effects in vitro: a potential AGE sequestration therapy for diabetic nephropathy? Mol Med. 2001 Nov;7(11):737-47. PMID: 11788787; PMCID: PMC1950004.
Advanced Glycation urinary protein -bound biomarkers and severity of diabetic nephropathy in man
Type of Study: Cross Sectional/ In Vivo
Sample Size: 68
Detailed Summary: In patients who have diabetic nephropathy is increased in patients who have diabetic nephropathy. In patients who had Type 1 and Type 2 Diabetes, the amount of serum AGE and the urine AGE was measured in both patients. Patients who suffered from both Type 1 and Type 2 Diabetes, there was a clear correlation between the amount of albuminuria and the amount of AGE proteins that was found in the urine. In patients with Type 2 Diabetes, they had a compound called urinary methylglyoxal which is an AGE intermediate. This method can potentially be used as a therapeutic test to see and screen people for AGE which may correlate with albuminuria diagnosis presently or in the future.
Coughlan MT, Patel SK, Jerums G, Penfold SA, Nguyen TV, Sourris KC, Panagiotopoulos S, Srivastava PM, Cooper ME, Burrell LM, Macisaac RJ, Forbes JM. Advanced glycation urinary protein-bound biomarkers and severity of diabetic nephropathy in man. Am J Nephrol. 2011;34(4):347-55. doi: 10.1159/000331064. Epub 2011 Aug 26. PMID: 21876347; PMCID: PMC3182043.
Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy?
Impact Factor: 2.4
Level of Evidence: IV
Sample Size: 16 rodents
Study type: Rat Study
Methods: 16 Sprague-Dawley Rates were taken and given an injection of streptozocin and were injected with long-acting insulin. The kidneys were taken out of the rats after the rats had undergone of about 32 weeks of a diabetic state. The two kidneys were used for slightly different purposes. One kidney was used for measurement of the MMP-7 activity using a RNeasy kit. The other kidney was used for the immunohistochemical purposes.
Results: When the mesangial cells were taken and introduced to advanced age glycation products there was a decrease in the MMP-7 gene. To provide a control, there as another set of cells that were introduced to aminoguanidine to prevent the glycation. The same pattern was seen with the introduction of TGF-B.
Conclusion: The degradation of the matrix of kidney cells may be an indicator of renal disease. There are two enzymes that are responsible for this degradation which are the MMPs and the plasma plasminogen activating system. This study shows that specifically MMP7 protein was decreased in patients thar were suffering from kidney disease. Aminoguanidine was used to block the AGE and was used as a control measure in this study
McLennan SV, Kelly DJ, Schache M, Waltham M, Dy V, Langham RG, Yue DK, Gilbert RE. Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy? Kidney Int. 2007 Aug;72(4):481-8. doi: 10.1038/sj.ki.5002357. Epub 2007 Jun 6. PMID: 17554258.