Role ofO-linkedN-acetylglucosamine modification in diabetic nephropathy

Abstract

Increased O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is a known contributor to diabetes; however, its relevance in diabetic nephropathy (DN) is poorly elucidated. Here, we studied the process and enzymes of O-GlcNAcylation with a special emphasis on Akt-endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP)72 signaling. Since tubular injury is the prominent site of DN, the effect of hyperglycemia was first measured in proximal tubular (HK2) cells cultured in high glucose. In vivo O-GlcNAcylation and protein levels of O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), phosphorylated (p)Akt/Akt, peNOS/eNOS, and HSP72 were assessed in the kidney cortex of streptozotocin-induced diabetic rats. The effects of various renin-angiotensin-aldosterone system (RAAS) inhibitors were also evaluated. In proximal tubular cells, hyperglycemia-induced OGT expression led to increased O-GlcNAcylation, which was followed by a compensatory increase of OGA. In parallel, peNOS and pAkt levels decreased, whereas HSP72 increased. In diabetic rats, elevated O-GlcNAcylation was accompanied by decreased OGT and OGA. RAAS inhibitors ameliorated diabetes-induced kidney damage and prevented the elevation of O-GlcNAcylation and the decrement of pAkt, peNOS, and HSP72. In conclusion, hyperglycemia-induced elevation of O-GlcNAcylation contributes to the progression of DN via inhibition of Akt/eNOS phosphorylation and HSP72 induction. RAAS blockers successfully inhibit this process, suggesting a novel pathomechanism of their renoprotective action in the treatment of DN.

RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

“…In line with our previous studies, we also observed severe structural and functional kidney damage in diabetic animals, which was improved by all RAASi (Banki et al 2012). According to the literature and our previous results, this renoprotection goes beyond decreasing blood pressure and can be related to other factors like lower oxidative stress (Fiordaliso et al 2006) or O-GlcNAc levels (Gellai et al 2016).…”

“…; Gellai et al . ). Some of these highlight the exceptional role of aldosterone antagonists (Taira et al .…”

“…Several studies demonstrate that various RAASi effectively decrease renal functional and structural damage in DM (Mifsud et al 2001;Osicka et al 2001;Gellai et al 2016). Some of these highlight the exceptional role of aldosterone antagonists (Taira et al 2008;Banki et al 2012), although the molecular pathways involved in their renoprotective effect are still not fully understood.…”

Nutrient regulation of signaling and transcription

“…Increased O-GlcNAcylation of cytoskeletal proteins is closely associated with the morphological changes in the podocyte foot processes in the glomerulus and in microvilli of proximal tubules in the diabetic kidney (252). Hyperglycemia-induced elevation of O-GlcNAcylation also contributes to the progression of diabetic nephropathy via inhibition of AKT/eNOS phosphorylation and HSP72 induction (253).…”

Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1

“…Ohtsubo et al (10) reported that human pancreatic bcell-specific GnT-4a glycosyltransferase, which generates the core b1-4 GlcNAc linkage in N-glycans, has a protective effect against diabetes by increasing GLUT2 expression and maintaining insulin secretion. Differences of glycosylation, including O-GlcNAcylation, were reported to contribute to the progression of DKD in rats (11,12). There have been few reports about differences of glycosylation in patients with DKD because of technical obstacles to glycan analysis as a result of the complicated structures of these molecules and the time-consuming processes required for mass spectrometry (MS).…”