Abstract
AimsThe 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 methodsTo 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.ResultsDespite 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.ConclusionsThese studies indicate that increased podocyte expression of oligosaccharyltransferase‐48 kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Highlights
There is a rising global pandemic of diabetes,[1,2] defined by persistent hyperglycaemia, a principal risk factor for the development of concomitant chronic complications.[3,4] the numbers of individuals with diabetic kidney disease (DKD), a major complication, are burgeoning
We have shown for the first time that increasing OST48 in a podocyte-specific manner decreased glomerular filtration and caused podocyte structural damage including foot process effacement, leading to glomerulosclerosis and tubulointerstitial fibrosis, and some parameters were further exacerbated by diabetes
Increases in OST48 in podocytes were marked by increased podocyte-specific Advanced glycation end products (AGEs) uptake resulting in oxidative and endoplasmic reticulum stress, which is independent of changes to the N-glycosylation machinery and subsequent kidney functional and structural decline (Figure 7), where previously it has been shown that AGE uptake into cultured podocytes induces hypertrophy[41] and apoptosis.[42]
Summary
There is a rising global pandemic of diabetes,[1,2] defined by persistent hyperglycaemia, a principal risk factor for the development of concomitant chronic complications.[3,4] the numbers of individuals with diabetic kidney disease (DKD), a major complication, are burgeoning. Advanced glycation end products (AGEs) are a heterogeneous and complex group of non-enzymatic, post-translational modifications to amino acids and proteins, which include haemoglobin A1C (HbA1C) a clinical marker used for the diagnosis of diabetes. Their endogenous formation can be exacerbated by chronic hyperglycaemia and oxidative stress 7 and the accumulation of AGEs occurs at an accelerated rate in diabetes.[8,9] Increases in AGE formation on skin collagen10–12 and within the circulation[13,14] predict poor prognosis for patients with diabetes including increased risk for kidney and cardiovascular disease. We examined if facilitating greater AGE clearance via modestly increasing podocyte-specific OST48 expression could attenuate the development and progression of DKD
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