PROBLEM: Therapeutic translation of T1D has been hampered by preclinical reproducibility
NOVEL APPROACH: We targeted the deficiency in circulating sRAGE (an antagonist to the receptor for advanced glycation end products ) levels prediabetes by short-term administration of recombinant human sRAGE with the aim of preventing diabetes onset in mice
FINDINGS: Short-term administration of sRAGE protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (Tregs) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.
PROBLEM: 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 are early contributors to diabetic kidney disease and could be a target for reno-protection.
NOVEL APPROACH: 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.
FINDINGS: 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. These studies indicate that increased podocyte expression of oligosaccharyltransferase-48kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Josephine Forbes is the recipient of the prestigious TJ Neale Award, as well as the following grants:
Professor Josephine Forbes is a Program Leader of the Chronic Disease Biology and Care research theme at Mater and a National Health and Medical Research Council (NHMRC) Senior Research Fellow. Josephine leads the Glycation and Diabetes Complications Research Group at Mater Research with a team of 10 researchers. Josephine is the author of over 160 scientific publications with her research currently focused on diabetes and its’ complications.
Josephine’s lab is investigating new treatments for diabetes and the devastating chronic complications associated with it such as kidney disease, blindness, amputations and heart disease. With this research, Josephine aims to build a greater understanding of the biological basis of diabetes in connection with a broad range of chronic diseases and develop preventative strategies and innovative treatments to improve patient outcomes.