Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney
Aowen Zhuang1,2, Felicia Y T Yap3,4, Domenica McCarthy1
1Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
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-48 kDa 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 urinary-renal 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.
Insights
Increasing oligosaccharyltransferase-48 kDa subunit (OST48) expression enhanced AGE clearance in diabetic mice but did not improve kidney function. However, it did improve insulin secretion, suggesting further research is needed.
Area of Science:
- Nephrology
- Endocrinology
- Metabolic Diseases
Background:
- Advanced glycation end products (AGEs) accumulation is linked to diabetic kidney disease (DKD) progression.
- Oligosaccharyltransferase-48 kDa subunit (OST48) is an AGE clearance receptor with potential therapeutic relevance in DKD.
Purpose of the Study:
- To investigate if increasing OST48 expression could mitigate DKD by enhancing AGE clearance.
- To evaluate the impact of global OST48 overexpression on kidney function and structure in a diabetic mouse model.
Main Methods:
- Male heterozygous knock-in mice overexpressing the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) gene and littermate controls were used.
- Mice were subjected to diabetes induction (streptozotocin) or no diabetes and followed for 24 weeks.
- Kidney function, AGE levels, fibrosis, and insulin secretion parameters were assessed.
Main Results:
- Global OST48 overexpression increased glomerular OST48 and renal AGE excretion but did not alter circulating or renal AGE concentrations.
- Diabetes induced kidney damage, including reduced glomerular filtration rate, albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis.
- In diabetic mice, OST48 overexpression exacerbated tubulointerstitial fibrosis but improved insulin effectiveness, acute insulin secretion, and fasting insulin levels.
Conclusions:
- Globally increasing OST48 expression facilitated AGE clearance but provided no discernible benefits for kidney function or structure in diabetic mice.
- The observed improvements in insulin secretion in OST48-overexpressing diabetic mice warrant further investigation due to their dissociation from kidney outcomes.
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