Abstract
A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs.
Highlights
Diabetes is characterized by chronic hyperglycemia and the development of diabetes-specific microvascular pathology[3] involving advanced glycation end products (AGEs), resulting from hyperglycemia-elicited metabolic and hemodynamic derangements, which have been proven to contribute to vascular complications in diabetes[4]
RhoA was activated by AGEs after 3 hours of Rat glomerular endothelial cells (rGECs) stimulation (Fig. 1A)
AGEs stimulate the secretion of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1)
Summary
Diabetes is characterized by chronic hyperglycemia and the development of diabetes-specific microvascular pathology[3] involving advanced glycation end products (AGEs), resulting from hyperglycemia-elicited metabolic and hemodynamic derangements, which have been proven to contribute to vascular complications in diabetes[4]. It was reported that ROCK is critical in controlling migration, proliferation, cell apoptosis/survival, gene transcription and differentiation[7]. The role of the RhoA/ROCK pathway in the regulation of adhesion and inflammation in the glomerulus in DN has not yet been clarified. The endothelium are divided into four steps: chemotaxis, adhesion, transformation and shuttling. These biological behaviors require adhesion molecules and chemokines. The endothelium plays a critical role in adhesion and migration. ICAM-1 and MCP-1 were assessed to determine the influence of AGEs on adhesion and the inflammatory infiltration of GECs. The role of RhoA/ROCK signaling in db/db mice was determined to evaluate the mechanism of inflammatory cell infiltration in DN
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