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      Tubular CD146 Expression in Nephropathies Is Related to Chronic Renal Failure

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          Background: CD146, a member of the immunoglobulin superfamily, is mainly expressed at the endothelial junction. The soluble form of CD146 is increased in the serum of patients with chronic renal failure. The aim of the study was to investigate CD146 expression on biopsies of normal kidney and nephropathies. Methods: We did an immunohistochemical analysis of 10 normal renal tissues and 126 patients with nephropathies. Results: The mean age of the patients was 47.5 ± 18 years with 65% of men. At the time of the biopsy, 73 patients (57.9%) had a renal failure and the mean proteinuria was 3.3 ± 2.9 g/24 h. Inflammatory syndrome was present in 60 (47.6%) patients. Fibrous interstitial changes from minimal lesions to diffuse lesions were seen in 105 (83.3%) biopsies; the mean glomerulosclerosis index was 16.9 ± 19.7%. Normal kidneys showed CD146 staining on endothelial cells, smooth muscle cells, and mesangium. Normal tubular cells were not stained. If endocapillary proliferation was present, the mesangial CD146 expression was higher. This mesangial expression correlated with proteinuria (p = 0.007) and not with renal failure (p = 0.07). A de novo expression on tubular cells was found in 53 patients (42%) and this expression correlated with age (p < 0.001), male sex (p = 0.04), glomerulosclerosis (p < 0.001), interstitial fibrosis (p < 0.001), and renal failure (p < 0.001). Conclusion: Renal CD146 expression is of interest for determining the pathogenesis of mesangial alterations during glomerular injuries and of tubular phenotypic changes during chronic renal failure.

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          Most cited references 22

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          A role for uric acid in the progression of renal disease.

          Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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            Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion.

            CD146 is a cell-surface molecule belonging to the immunoglobulin superfamily and expressed in all types of human endothelial cells. Confocal and electron microscopic analysis of confluent human umbilical vein endothelial cells (HUVECs) were used to demonstrate that CD146 is a component of the endothelial junction. Double immunolabeling with vascular endothelial cadherin showed that CD146 is localized outside the adherens junction. Moreover, CD146 expression is not restricted to the junction, since part of the labeling was detectable at the apical side of the HUVECs. Interestingly, cell-surface expression of CD146 increased when HUVECs reached confluence. In addition, the paracellular permeability of CD146-transfected fibroblast cells was decreased compared with that of control cells. Finally, CD146 colocalized with actin, was partly resistant to Triton X-100 extraction, and had its expression altered by actin-disrupting agents, indicating that CD146 is associated with the actin cytoskeleton. These results show the regulated expression of CD146 at areas of cell-cell junction and strongly suggest involvement of CD146 as a mediator of cell-cell interaction.
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              A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth.

              The goal of our study was to raise monoclonal antibodies (mAbs) against endothelial cell-surface proteins specific for tumor vasculature. Here, we describe the generation and intensive characterization of mAb AA98, including its functional properties and its antigen identification. In our study, an enhanced mAb AA98 immunoreactivity was observed on stimulated human umbilical vein endothelial cells (HUVECs). In addition, mAb AA98 showed remarkably restricted immunoreactivity against intratumoral neovasculature compared with blood vessels of normal tissues. We identified the AA98 antigen as human CD146, an adhesion molecule belonging to the immunoglobulin superfamily. Data from in vitro experiments imply structural and signaling functions for endothelial CD146; however, the role of CD146 in vivo is largely unknown. Here, we show that mAb AA98 displays antiangiogenic properties in vitro and in vivo. Proliferation and migration of HUVECs were inhibited by mAb AA98 as was angiogenesis in chicken chorioallantoic membrane (CAM) assays and tumor growth in 3 xenografted human tumor models in mice. Our data provide new insights into the function of CD146 on endothelial cells, validate CD146 as a novel target for antiangiogenic agents, and demonstrate that mAb AA98 has potential as a diagnostic and therapeutic agent in vascular and cancer biology.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2005
                10 February 2005
                : 99
                : 4
                : e105-e111
                aEA 3281, Faculty of Medicine, bINSERM EMI 0019, Faculty of Pharmacy, and cDepartment of Nephrology, Conception Hospital, Marseille, France
                83890 Nephron Exp Nephrol 2005;99:e105–e111
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 3, References: 30, Pages: 1
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Tubular cells, Kidney, Chronic renal failure, CD146, Proteinuria


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