DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

Hoverfelt, A.; Sallinen, Riitta; Söderlund, Jenny; Forsblom, Carol; Pettersson-Fernholm, Kim; Parkkonen, Maija; Groop, Per Henrik; Wessman, Maija

doi:10.1007/s00125-010-1771-3

Cited by 11 publications

(9 citation statements)

References 13 publications

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“…This contrasts a smaller study in T1D individuals which identified low levels of AGE-R1 mRNA in circulating mononuclear cells in conjunction with elevated levels of serum AGEs, in those individuals with nephropathy [49]. It is worth noting however, that despite not reaching significance, the FinnDiane SNP array identified a trend towards an association between a SNP (rs2170336) in DDOST and DN in individuals with T1D [55]. Therefore, this may be resolved by other longitudinal studies in DN and in the expansion of the sample size in future genetic screens.…”

Section: Age-r1 An Unusal Receptor Involved In Diabetic Nephropathycontrasting

confidence: 60%

“…A SNP array from the FinnDiane population study inferred that there was no association between SNPs of the AGE-R1 gene, DDOST with nephropathy development in individuals with T1D [55]. This contrasts a smaller study in T1D individuals which identified low levels of AGE-R1 mRNA in circulating mononuclear cells in conjunction with elevated levels of serum AGEs, in those individuals with nephropathy [49].…”

Section: Age-r1 An Unusal Receptor Involved In Diabetic Nephropathymentioning

confidence: 90%

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Diabetic kidney disease: a role for advanced glycation end-product receptor 1 (AGE-R1)?

Zhuang

Forbes

2016

Glycoconj J

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Diabetic patients are postulated to be in a perpetual state of oxidative stress and inflammation at sites where chronic complications occur. The accumulation of AGEs derived from both endogenous and exogenous sources (such as the diet) have been implicated in the development and progression of diabetic complications, particularly nephropathy. There has been some interest in investigating the potential for reducing the AGE burden in chronic disease, through the action of AGE "clearance" receptors, such as the advanced glycation end-product receptor 1 (AGE-R1). Reducing the burden of AGEs has been linked to attenuation of inflammation, slower progression of diabetic complications (in particular vascular and renal complications) and has been shown to extend lifespan. To date, however, there have been no direct investigations into whether AGE-R1 has any role in modulating normal kidney function, or specifically during the development and progression of diabetes. This mini-review will focus on the recent advances in knowledge around the mechanistic function of AGE-R1 and the implications of this for the pathogenesis of diabetic kidney disease.

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Section: Age-r1 An Unusal Receptor Involved In Diabetic Nephropathycontrasting

confidence: 60%

Section: Age-r1 An Unusal Receptor Involved In Diabetic Nephropathymentioning

confidence: 90%

Diabetic kidney disease: a role for advanced glycation end-product receptor 1 (AGE-R1)?

Zhuang

Forbes

2016

Glycoconj J

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“…There exist AGE receptors 1, 2, and 3 (encoded by dolichyl diphospho-oligosaccharide protein glycosyltransferase, protein kinase C substrate 80K-H, and lectin galactoside-binding soluble 3, respectively) (Hoverfelt et al, 2010). RAGE protein is massively up-regulated during diabetes in peripheral nerve and ganglia.…”

Section: Advanced Glycation End-products Inhibitors (Retinopathy mentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacol Rev

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“…This contrasts a smaller study in T1D individuals which identified low levels of AGE-R1 mRNA in circulating mononuclear cells in conjunction with elevated levels of serum AGEs, in those individuals with nephropathy 49 . It is worth noting however, that despite not reaching significance, the FinnDiane SNP array identified a trend towards an association between a SNP (rs2170336) in DDOST and DN in T1D 55 .…”

Section: Age-r1 An Unusual Receptor Involved In Diabetic Nephropathymentioning

confidence: 91%

“…Evidence linking AGE-R1 and diabetic nephropathy in clinical studies is sparse, where the only two studies that investigated this association have contradicting conclusions. A SNP array from the FinnDiane population study inferred that there was no association between SNPs of the AGE-R1 gene, DDOST with nephropathy development in individuals with T1D 55 . This contrasts a smaller study in T1D individuals which identified low levels of AGE-R1 mRNA in circulating mononuclear cells in conjunction with elevated levels of serum AGEs, in those individuals with nephropathy 49 .…”

Section: Age-r1 An Unusual Receptor Involved In Diabetic Nephropathymentioning

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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DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

Cited by 11 publications

References 13 publications

Diabetic kidney disease: a role for advanced glycation end-product receptor 1 (AGE-R1)?

Diabetic kidney disease: a role for advanced glycation end-product receptor 1 (AGE-R1)?

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

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

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