Oligosaccharyltransferase-48 as a Novel Mediator of Chronic Kidney Disease in Diabetes — ASN Events

Oligosaccharyltransferase-48 as a Novel Mediator of Chronic Kidney Disease in Diabetes (#261)

Aowen Zhuang 1 , Brooke E Harcourt 1 , Karly C Sourris 2 , Sally A Penfold 2 , Amelia K Fotheringham 1 , Domenica McCarthy 1 , Peter Thorn 3 , Josephine M Forbes 1
  1. Glycation and Diabetes Complications, Mater Research, Brisbane, Queensland, Australia
  2. Glycation, Nutrition and Metabolism, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
  3. School of Medicine, University of Queensland, Brisbane, Queensland, Australia

Aims

1.       To characterise the physical and biochemical characteristics of both the OST-48 transgenic knock-in models.

2.       To investigate if changes in OST-48 expression in mice affects kidney function and insulin sensitivity in the presence or absence of diabetic kidney disease.

 Background

Kidney disease leading to heart attacks and strokes affects up to one third of Australian individuals with diabetes and is one of the most deadly and poorly understood chronic complications1. There is recent evidence that changes leading to the accumulation of inappropriately folded proteins severely impacts kidney function2, 3. This project investigates the role of N-glycosylation, which is controlled by a subunit called oligosaccharyltransferase-48 (OST-48) in mammals and is necessary for the correct folding and trafficking of many proteins.

 Methods

Male heterozygous global OST-48 transgenic knock-in mice C57Bl/6-Tg(Ubi-Cre, DDOST) (OST-48Tg), podocyte specific C57Bl/6-Tg(Pod-Cre, DDOST) (OST-48Tg Pod) and littermate controls (WT) (N=8/group) were randomised to diabetes by low dose streptozotocin (55mg/kg/day for 5 days) or no diabetes and followed for 24 weeks (OST-48Tg) or 12 weeks (OST-48Tg Pod). Physical characteristics were measured throughout the study and biochemical properties were identified through metabolic caging. We then examined kidney function through the rate of albumin excretion measured by ELISA and the ratio of creatinine clearance by HPLC. Finally we investigated the insulin sensitivity of these mice through IPGTT and IPITT.

Results

Global OST-48Tg mice had a decrease in insulin sensitivity by the study completion. Moreover kidney function and health in both transgenic models was severely exacerbated by diabetes developing into end-stage kidney disease.

Conclusions

This preliminary investigation has demonstrated that functional OST-48 may play a role in normal kidney function and insulin sensitivity, particularly when exacerbated by diabetes. Therefore, we suggest that the alteration of functional OST-48 may play a role in kidney function which is further exacerbated by diabetes.

  1. Cass A, Chadban S, Gallagher M, Howard K, Jones A, McDonald S, Snelling P and White S: The Economic Impact of End-Stage Kidney Disease in Australia: Projections to 2020. Kidney Health Australia, 2010
  2. Lindenmeyer MT, Rastaldi MP, Ikehata M, Neusser MA, Kretzler M, Cohen CD and Schlondorff D: Proteinuria and hyperglycemia induce endoplasmic reticulum stress. J Am Soc Nephrol 2008;19:2225-2236
  3. Liu G, Sun Y, Li Z, Song T, Wang H, Zhang Y and Ge Z: Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease. Biochem Biophys Res Commun 2008;370:651-656
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