High glucose and diabetes modulate cellular proteasome function: Implications in the pathogenesis of diabetes complications

Abstract

The precise link between hyperglycemia and its deleterious effects on retinal and kidney microvasculature, and more specifically loss of retinal perivascular supporting cells including smooth muscle cell/pericytes (SMC/PC), in diabetes are not completely understood. We hypothesized that differential cellular proteasome activity contributes to sensitivity of PC to high glucose-mediated oxidative stress and vascular rarefaction. Here we show that retinal endothelial cells (EC) have significantly higher proteasome peptidase activity compared to PC. High glucose treatment (HGT) increased the level of total ubiquitin-conjugated proteins in cultured retinal PC and EC, but not photoreceptor cells. In addition, in vitro proteasome activity assays showed significant impairment of proteasome chymotrypsin-like peptidase activity in PC, but not EC. The PA28-α/-β and PA28-β/-γ protein levels were also higher in the retina and kidney glomeruli of diabetic mice, respectively. Our results demonstrate, for the first time, that high glucose has direct biological effects on cellular proteasome function, and this modulation might be protective against cellular stress or damage induced by high glucose.

Regulated in Development and DNA Damage 1 Is Necessary for Hyperglycemia-induced Vascular Endothelial Growth Factor Expression in the Retina of Diabetic Rodents

“…The abundance of any given protein in a cell (aka gene expression) is the sum of transcription, mRNA stability, mRNA translation, and protein degradation. Whereas the pathological consequences of altered transcription and degradation have received much attention (34,35), the effect of diabetes on mRNA translation has been less well explored, despite the fact that next-generation sequencing and large-scale proteomics demonstrate a dominant contribution of mRNA translation to gene expression (36). We recently reported the existence of a diabetesinduced hyperglycemia-mediated shift in gene expression that was associated with down-regulation of cap-dependent and concomitant up-regulation of cap-independent mRNA translation in both STZ-treated mice and cells in culture (9).…”

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

“…Like any other eukaryotic protein, PHLPP also undergoes degradation via 26S proteasomal pathway. Insulinresistant conditions are marked with altered proteasomal degradation (Aghdam et al 2013). Overexpression of the deubiquitinating proteins poses serious threat to the cells via AKT inhibition.…”

The Role of Ubiquitination and Sumoylation in Diabetic Nephropathy

“…Studies found that members of UPS, cullin-1, cullin-3, and the 11S proteasome regulators PA28- β and PA28-g are definitely upregulated in intraglomerular capillaries of mice with DN [13]. …”