Zhang H, Schin M, Saha J, et al. Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0680, USA.
AJP Renal Physiology (Impact Factor: 3.25). 04/2010; 299(1):F91-8. DOI: 10.1152/ajprenal.00021.2010
Source: PubMed


Increased expression of the facilitative glucose transporter, GLUT1, leads to glomerulopathy that resembles diabetic nephropathy, whereas prevention of enhanced GLUT1 expression retards nephropathy. While many of the GLUT1-mediated effects are likely due to mesangial cell effects, we hypothesized that increased GLUT1 expression in podocytes also contributes to the progression of diabetic nephropathy. Therefore, we generated two podocyte-specific GLUT1 transgenic mouse lines (driven by a podocin promoter) on a db/m C57BLKS background. Progeny of the two founders were used to generate diabetic db/db and control db/m littermate mice. Immunoblots of glomerular lysates showed that transgenic mice had a 3.5-fold (line 1) and 2.1-fold (line 2) increase in GLUT1 content compared with wild-type mice. Both lines showed similar increases in fasting blood glucose and body weights at 24 wk of age compared with wild-type mice. Mesangial index (percent PAS-positive material in the mesangial tuft) increased 88% (line 1) and 75% (line 2) in the wild-type diabetic mice but only 48% (line 1) and 39% (line 2) in the diabetic transgenic mice (P < 0.05, transgenic vs. wild-type mice). This reduction in mesangial expansion was accompanied by a reduction in fibronectin accumulation, and vascular endothelial growth factor (VEGF) levels increased only half as much in the transgenic diabetic mice as in wild-type diabetic mice. Levels of nephrin, neph1, CD2AP, podocin, and GLUT4 were not significantly different in transgenic compared with wild-type mice. Taken together, increased podocyte GLUT1 expression in diabetic mice does not contribute to early diabetic nephropathy; surprisingly, it protects against mesangial expansion and fibronectin accumulation possibly by blunting podocyte VEGF increases.

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    ABSTRACT: SUMMARY: Podocyte loss is a common feature in human diabetes as well as in experimental diabetes in rodents. Almost all components of the diabetic milieu lead to serious podocyte stress, driving the cells towards cell cycle arrest and hypertrophy, detachment and apoptosis. Common pathway components induced by high glucose and advanced glycation end-products are reactive oxygen species, cyclin-dependent kinases (p27(Kip1)) and transforming growth factor-beta. In addition, mechanical stresses by stretch or shear forces, insulin deficiency or insulin resistance are independent components resulting in podocyte apoptosis and detachment. In this review, we discuss the common pathways leading to podocyte death as well as novel pathways and concepts of podocyte dedifferentiation and detachment that influence the progression of diabetic glomerulopathy.
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    ABSTRACT: Diabetic nephropathy (DN) represents a major public health cost. Tight glycemic and blood pressure control can dramatically slow, but not stop, the progression of the disease, and a large number of patients progress toward end-stage renal disease despite currently available interventions. An early and key event in the development of DN is loss of podocyte function (or glomerular visceral epithelial cells) from the kidney glomerulus, where they contribute to the integrity of the glomerular filtration barrier. Recent evidence suggests that podocytes can be the direct target of circulating hormones, lipids, and adipokines that are affected in diabetes. We review the clinical and experimental evidence implicating novel endocrine and metabolic pathways in the pathogenesis of podocyte dysfunction and the development of DN.
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