Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.

Zhuang, A.; Yap, F. Y.; McCarthy, D.; Leung, S. S.; Penfold, S. A.; Leung, C.; Sourris, K. C.; Harcourt, B.; Thallas-Bonke, V.; Coughlan, M. T.; Schulz, B.; Forbes, J.

doi:10.1101/710558

bioRxiv · 10.1101/710558

Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.

Zhuang, A.·Yap, F. Y.·McCarthy, D.·Leung, S. S.·Penfold, S. A.·Leung, C.·Sourris, K. C.·Harcourt, B.·Thallas-Bonke, V.·Coughlan, M. T.·Schulz, B.·Forbes, J.

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Abstract

The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n=9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinaryrenal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

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Zhuang, A., Yap, F. Y., McCarthy, D., Leung, S. S., Penfold, S. A., Leung, C., Sourris, K. C., Harcourt, B., Thallas-Bonke, V., Coughlan, M. T., Schulz, B., Forbes, J.. 2019-07-22. Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.. https://doi.org/10.1101/710558

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