AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study

Normand, Gabrielle; Lemoine, Sandrine; Villien, Marjorie; Bars, Didier Le; Mérida, Inès; Irace, Zacharie; Troalen, Thomas; Costes, Nicolas; Juillard, Laurent

doi:10.2337/dc18-0131

Cited by 14 publications

(12 citation statements)

References 14 publications

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“…Renal perfusion assessed (by PET) after meals containing high AGEs revealed significant increases. Oxidative stress was also slightly higher from baseline levels [81]. Inhibition of the AGE-RAGE complex by antagonists, such as linagliptin, proved to have a potent protective mechanism from renal damage in diabetes [82].…”

Section: Ages Diabetes and Their Related Disordersmentioning

confidence: 86%

“…Women with PCOS usually have low Vitamin D3. However, the vitamin is required for the sustainable functioning of ovarian follicles and oocyte development [81][82][83]. Vitamin D3 not only down-regulates the AGE-RAGE interaction, but also attenuates overexpression of RAGE mRNA, as AGE mimics hormones and disrupts its expression ( Figure 5a), making it an important parameter to understand the pathophysiology of PCOS [88,98,[111][112][113][114]].…”

Section: Ages and Women's Healthmentioning

confidence: 99%

“…Crosslinking of skin collagen, carotid thickening, ischemic heart attack, chronic and end-stage renal disease, diabetic retinopathy, uremic cardiomyopathy, alterations in lipo-and apolipoproteins, inactivation of nitric oxide [64,[70][71][72][73][74][75][76][77][78][79][80][81][82][83] Alzheimer's disease, certain neurodegenerative diseases, advance stages of amyloidosis β-amyloid protein plaques, cerebrovascular amyloid deposits, neurofibrillary tangles [85][86][87] Ovarian dysfunction, polycystic ovarian syndrome, anovulation, infertility Increased testosterone, thyroid hormones, androgens, anti-Mullerian hormone, disruptive steroidogenesis [71,92,108] Inflammation, allergies, asthma, multiple sclerosis, Crohn's disease Activating unprogrammed cell death, altering immune responses by monocytes, basophils, macrophages, and dendritic cells, might create false allergic responses [75,76,114,115] Dental disorders Periodontitis leading to tooth loss due to gum infection might increase the risk of heart and lung diseases [116]…”

Section: Diabetesmentioning

confidence: 99%

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Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

et al. 2019

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The Maillard reaction is a simple but ubiquitous reaction that occurs both in vivo and ex vivo during the cooking or processing of foods under high-temperature conditions, such as baking, frying, or grilling. Glycation of proteins is a post-translational modification that forms temporary adducts, which, on further crosslinking and rearrangement, form permanent residues known as advanced glycation end products (AGEs). Cooking at high temperature results in various food products having high levels of AGEs. This review underlines the basis of AGE formation and their corresponding deleterious effects on the body. Glycated Maillard products have a direct association with the pathophysiology of some metabolic diseases, such as diabetes mellitus type 2 (DM2), acute renal failure (ARF), Alzheimer’s disease, dental health, allergies, and polycystic ovary syndrome (PCOS). The most glycated and structurally abundant protein is collagen, which acts as a marker for diabetes and aging, where decreased levels indicate reduced skin elasticity. In diabetes, high levels of AGEs are associated with carotid thickening, ischemic heart disease, uremic cardiomyopathy, and kidney failure. AGEs also mimic hormones or regulate/modify their receptor mechanisms at the DNA level. In women, a high AGE diet directly correlates with high levels of androgens, anti-Müllerian hormone, insulin, and androstenedione, promoting ovarian dysfunction and/or infertility. Vitamin D3 is well-associated with the pathogenesis of PCOS and modulates steroidogenesis. It also exhibits a protective mechanism against the harmful effects of AGEs. This review elucidates and summarizes the processing of infant formula milk and the associated health hazards. Formulated according to the nutritional requirements of the newborn as a substitute for mother’s milk, formula milk is a rich source of primary adducts, such as carboxy-methyl lysine, which render an infant prone to inflammation, dementia, food allergies, and other diseases. We therefore recommend that understanding this post-translational modification is the key to unlocking the mechanisms and physiology of various metabolic syndromes.

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Section: Ages Diabetes and Their Related Disordersmentioning

confidence: 86%

Section: Ages and Women's Healthmentioning

confidence: 99%

Section: Diabetesmentioning

confidence: 99%

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Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

et al. 2019

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“…We observed that OST48 facilitation of podocyte AGE accumulation resulted in a cascade of ER stress culminating in podocyte foot process effacement, GBM expansion, and renal functional decline. Increasing the urinary flux of AGEs has however been previously shown to impair renal function in both healthy humans [41,48] and early in the development of diabetic kidney disease in rodent models [35,49].…”

Section: Discussionmentioning

confidence: 99%

The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion in experimental diabetic kidney disease via promotion of endoplasmic reticulum stress

Zhuang

Yap

McCarthy

et al. 2019

Preprint

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The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection. To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter. Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products. These studies indicate that increased podocyte expression of oligosaccharyltransferase-48kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.

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“…Increasing the urinary flux of AGEs has however been previously shown to impair renal function in both healthy humans 4,287 and early in the development of diabetic kidney disease in rodent models 136,288 .…”

Section: Discussionmentioning

confidence: 99%

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

Zhuang¹

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The protein oligosaccharyltransferase-48 (OST48/AGE-R1) is integral to protein N-glycosylation in the endoplasmic reticulum (ER) but is also postulated to act as a membrane localised clearance receptor for advanced glycation end-products (AGE). AGE accumulation is implicated in liver injury, diabetic kidney disease and diabetes-associated metabolic disorders. To date, however, there has been minimal investigation into the role of OST48 in kidney and liver function under either physiological or diabetic conditions. Here we have used both global (DDOST+/-) and targeted (podocyte specific; DDOST+/-Pod-Cre ) knock-in mouse models to induce subtle increases in OST48.The burden of OST48 ligands, AGEs in these models, was modified by either dietary intervention or by the induction of diabetes to delineate the effects of increasing OST48 on the kidney and liver metabolome and proteome. Given previous studies, our postulate was that increasing OST48 would improve liver and kidney function in diabetes by facilitating removal of AGEs from the body.In the first study, we examined hepatic function and structure following global knock in of OST48 in combination with a therapeutic reduction in dietary AGE intake. Global knock-in of OST48 increased protein OST48 in the gastrointestinal tract, where it was highest in the duodenum. Both increasing gastrointestinal OST48 expression and/or greater consumption of AGEs modestly impaired liver function resulting in hepatic fibrosis. However, a combination of both high AGE dietary consumption and increased OST48 expression significantly exacerbated liver injury, but this was in the absence of steatosis. Interestingly, DDOST+/-mice had increased portal vein delivery and accumulation of hepatic AGEs which were associated with central adiposity, insulin secretory defects, shifting of fuel usage to fatty and keto-acids, and hepatic glycogen accumulation. These culminated in hepatomegaly along with hepatic ER and oxidative stress. This work is significant in that it revealed a novel role of the OST48 and AGE axis as a two-hit model of hepatic injury through ER stress, changes in fuel utilisation and impaired glucose tolerance.Our second and third studies aimed to delineate the physiological role of OST48 in the kidney through a global and podocyte-specific knock-in of OST48. Firstly, we investigated whether increased AGE excretion facilitated by modest increases in OST48, could prevent the development of diabetic kidney disease. This body of work is particularly significant, as to date there have been no studies examining whether elevating OST48 in diabetes is reno-protective, despite associative studies suggesting that a loss of OST48 is a pathological contributor to diabetes complications.

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AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study

Abstract: Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.

Cited by 14 publications

References 14 publications

Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion in experimental diabetic kidney disease via promotion of endoplasmic reticulum stress

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

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