Leukocyte Recruitment and Vascular Injury in Diabetic Nephropathy

Abstract

Different types of activated leukocytes play a crucial role in the pathogenesis of most kidney diseases from acute to chronic stages; however, diabetic nephropathy was not considered an inflammatory disease in the past. This view is changing now because there is a growing body of evidence implicating inflammatory cells at every stage of diabetic nephropathy. Renal tissue macrophages, T cells, and neutrophils produce various reactive oxygen species, proinflammatory cytokines, metalloproteinases, and growth factors, which modulate the local response and increase inflammation within the diabetic kidney. Although the precise mechanisms that direct leukocyte homing into renal tissues are not fully identified, it has been reported that intercellular adhesion molecule-1 and the chemokines CCL2 and CX3CL1 probably are involved in leukocyte migration in diabetic nephropathy. This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.J Am Soc Nephrol 17: 368 -377, 2006368 -377, . doi: 10.1681 Diabetic NephropathyDiabetic nephropathy (DN) is the leading case of end-stage renal failure (review in reference [1]). The major features of DN include albuminuria, progressive reduction of GFR, and increased risk for cardiovascular diseases (1-3). DN is associated with the expansion of mesangial cells and development of characteristic features of renal injury, such as thickening of the glomerular basement membrane. In the end, glomerulosclerosis and tubulointerstitial fibrosis are observed in patients with diabetic pathology (4,5). Approximately 30% of patients with type 1 diabetes develop DN (6,7). Barkis et al. (8) reported that approximately 25 to 30% of patients with type 2 diabetes will develop overt DN. Recently, several murine models of DN were developed (review in reference [9]). The well-established streptozotocin (STZ)-induced (10 -14) and nonobese diabetic (NOD) (15-18) mouse models are most commonly used to study type 1 diabetes. A few models of type 2 diabetes include db/db mice (19,20), ob/ob mice (21), agouti mice on different backgrounds (22,23), and C57BL/6 on high-fat diet (24). Although some features such as the absence of renal failure complicate the interpretations of the studies in murine models, several distinct stages of DN can be detected in murine models (9). Genetically deficient mice that lack different inflammatory molecules are expected to help dissect the molecular mechanisms of initiation and development of DN.It is well known that hyperglycemia is a major factor risk for DN (25), but hyperglycemia does not account for all changes that are observed in renal tissues (26). It has been suggested that advanced glycation end products (AGE) (27-30), activation of protein kinase C (31), and overexpression of different growth factors (32) are associated with the pathogenesis of DN. Extracellular matrix accumulation is one of the hallmarks in the development of the disease that leads to the ...

The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

“…Although diabetic nephropathy is not often considered an inflammatory disease, 1 there is strong evidence that macrophage infiltration not only is increased but may have a role in mediating local injury (mesangiolysis) and fibrosis. [3][4][5]7 Our hypothesis was that a state of endothelial dysfunction might result in greater macrophage infiltration or activation.…”

“…1,2 The macrophage is one of the central mediators of renal vascular inflammation, and its accumulation is a characteristic feature of diabetic nephropathy. [3][4][5] Macrophages have been shown to cause proteinuria and mesangial cell injury in experimental glomerulonephritis.…”

“…3,11 MCP-1 and ICAM-1 may coordinate to stimulate leukocyte chemotaxis and adhesion, respectively. 1,2 Although MCP-1 and ICAM-1 are likely to be key factors in modulating the inflammatory response in diabetic renal disease, it also remains possible that other chemotactic factors may have contributory roles.…”

Effects of different LDL particles on inflammatory molecules in human mesangial cells

“…The role of oxidised LDLs in mediating tissue damage in the kidney has been extensively investigated: they mediate the production of adhesion molecules and the adhesion of monocytes to mesangial cells [4], the production of cytokines contributing to the infiltration and differentiation of monocytes [5], the induction of apoptosis [6], and the production of extracellular matrix components, all of which are fundamental pathological processes in the development and progression of glomerular diseases including focal glomerulosclerosis and diabetic nephropathy [7][8][9].…”

Effect of Diabetes on the Rat Renal Cortex and the Possible Protective Role of Vitamins C and E

“…Regarding inflammatory cells, the presence of leukocytic infiltration in diabetic renal tissue was previously reported. [39,40] Added that these immune cells may participate in the vascular injury encountered in diabetic nephropathy and could be considered as a crucial step in disease progression.…”