GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

Abstract

Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β₁, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

Hypothalamic-pituitary-adrenal axis activity is associated with the prevalence of chronic kidney disease in diabetic patients

“…High extracellular glucose activates a number of signaling cascade at the cellular level via GLUT1-facilitated transport of glucose. They sequentially cause accumulation of extracellular matrix protein in the mesangial space with mesangial expansion, thickening of the glomerular and tubular basement membranes, and tubulointerstitial fibrosis [33][34][35]. Importantly, the activation of the MR cascade related with the HPA axis may lead to progression of diabetic nephropathy, independent of the general mechanisms for CKD due to diabetes mellitus.…”

Role of advanced glycation end products in the onset of diabetic kidney disease complications

“…Mesangial cells cultured in hyperglycemic conditions showed increased expression of GLUT1, which is the main glucose transporter in mesangial cells 46,47 . In addition, these cells showed higher PKC activity and the subsequent stimulation of extracellular matrix proteins expression 47,48 . The increased expression of GLUT1 in vitro up regulated GLUT1 expression, through the activation of PKC and promoted the stimulation of extracellular matrix synthesis in mesangial cells.…”

“…The increased expression of GLUT1 in vitro up regulated GLUT1 expression, through the activation of PKC and promoted the stimulation of extracellular matrix synthesis in mesangial cells. The expression of GLUT1 seems to be the limiting step for the use of glucose by mesangial cells 48,49 . Angiotensin II (AII) also increases the expression of messenger RNA (mRNA) of GLUT1 in mesangial cells and GLUT2 (responsible for tubular reabsorption of glucose) also favored increased interstitial glucose, which is transported intracellularly by GLUT1 48,49 .…”

Beyond Proteinuria: Apoptosis and Vitamin D3 State in Children with Diabetic Nephropathy

“…Nephrons from proteinuric diabetic patients show that 71% of glomeruli display glomerulotubular junction abnormalities and 8-17% of glomeruli are atubular glomeruli [5].…”

“…In vitro and in vivo studies have shown that high glucose (HG) concentrations are associated with increased reactive oxygen species (ROS) production, inflammation which inhibits proximal tubular function and induces apoptosis. Apoptosis has been detected in renal proximal tubular cells (RPTCs) of diabetic mice and rats [5,6]. Moreover, in vitro data show the role of Vitamin D3 in rescuing kidney cells from apoptosis induced by glucose and albumin.…”