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The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion (alters structural composition)

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2021

Endocrinol Diabetes Metab. 2021 Jun 22;4(3):e00278. doi: 10.1002/edm2.278. eCollection 2021 Jul.

The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion (alters structural composition)

Aowen Zhuang , Felicia Y T Yap, Danielle J Borg, Domenica McCarthy, Amelia Fotheringham, Sherman Leung, Sally A Penfold, Karly C Sourris, Melinda T Coughlan, Benjamin L Schulz, Josephine M Forbes

Glycation and Diabetes Complications Mater Research Institute - The University of Queensland Translational Research Institute Woolloongabba Qld Australia. Faculty of Medicine University of Queensland St Lucia Qld Australia. Baker Heart and Diabetes Institute Melbourne Vic Australia. Department of Diabetes Central Clinical School Monash University Melbourne Vic Australia. School of Chemistry and Molecular Biosciences University of Queensland St Lucia Qld Australia.

Service type: Transgenic mice

Abstract

Aims: 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. Materials and methods: 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. Results: 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. Conclusions: These studies indicate that increased podocyte expression of oligosaccharyltransferase-48 kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function. Keywords: advanced glycation end‐product receptor 1; advanced glycation end‐products; diabetes; diabetic kidney disease; endoplasmic reticulum stress; oligosaccharyltransferase‐48 diabetic nephropathy.

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