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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      About Blood Purification: 3.0 Impact Factor I 5.6 CiteScore I 0.83 Scimago Journal & Country Rank (SJR)

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      Renoprotective effect of breviscapine through suppression of renal macrophage recruitment in streptozotocin-induced diabetic rats.

      Nephron. Experimental Nephrology
      Animals, Chemokine CCL2, analysis, Diabetes Mellitus, Experimental, drug therapy, physiopathology, Diabetic Nephropathies, prevention & control, Flavonoids, pharmacology, Intercellular Adhesion Molecule-1, Kidney Glomerulus, drug effects, pathology, Macrophages, Male, Oxidative Stress, Rats

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          Abstract

          Experimental and clinical evidence has consistently demonstrated that renal macrophage infiltration is one of the most important events for the progression of diabetic nephropathy. Breviscapine is a flavonoid extracted from the Chinese herb Erigeron breviscapus. Previously, it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study is to investigate whether the renoprotective effect of breviscapine is through suppression of renal macrophage recruitment in diabetic rats. Diabetes was induced bystreptozotocin injection, and breviscapine was administered orally at a dose of 20 mg/kg/day for 8 weeks. Control rats received vehicle or breviscapine with the same schedule. Breviscapine treatment markedly inhibited both an increase of albuminuria and glomeruli hypertrophy and tubulointerstitial injury without modifying mean arterial blood pressure and creatinine clearance. Levels of malondialdehyde and protein kinase C activities were markedly higher and antioxidant enzyme activities such as superoxide dismutase, catalase as well as glutathione peroxidase were significantly lower in the kidneys of diabetic rats than of the control group, breviscapine administration markedly remitted these changes. ED-1-positive cells and expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) in glomeruli and tubulointerstitium were all markedly elevated but were significantly reduced by breviscapine. Western blot analysis noted that the expression of transforming growth factor beta1 protein was increased 1.8-fold in the kidney in diabetic rats, breviscapine treatment could reduce increased expression of TGF-beta1 protein by 47%. This study describes a novel mechanism by which breviscapine confers a renoprotective effect. Copyright 2006 S. Karger AG, Basel.

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          Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

          Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
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            Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats.

            Diabetic glomerulosclerosis is defined by increased glomerular extracellular matrix (ECM) that is mainly synthesized by mesangial cells that underwent an activation mediated by cytokines and growth factors from various cellular origins. In this study, we tested whether macrophages could infiltrate the glomeruli and influence ECM synthesis in experimental diabetes. To test our hypothesis, we initially studied the dynamics of glomerular macrophage recruitment in streptozotocin-induced diabetic rats at days 1, 2, 4, 8, 15, and 30 by using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on isolated glomeruli and immunohistochemistry and morphometry. We then assessed the role of macrophages on the basis of the pharmacological modulation of their recruitment by insulin or ACE inhibitor treatments and by X-irradiation-induced macrophage depletion at days 8 and 30. Macrophages were recruited within the glomeruli at the very early phase of hyperglycemia by using RT-PCR CD14 detection from day 2 and by using ED1 immunohistochemistry from day 8. This glomerular macrophage infiltration was associated with an increase in alpha1-chain type IV collagen mRNA. In parallel, the diabetic glomeruli became hypertrophic with an increase in the mesangial area. Macrophage recruitment was preceded by or associated with an increased glomerular expression of vascular cell adhesion molecule 1, intracellular adhesion molecule 1, and monocyte chemoattractant protein 1, which contributes to monocyte diapedesis. Glomerular interleukin-1beta mRNA synthesis was also enhanced as early as day 1 and could be involved in the increase in ECM and adhesion molecule gene expressions. Insulin treatment and irradiation-induced macrophage depletion completely prevented the glomerular macrophage recruitment and decreased alpha1-chain type IV collagen mRNA and mesangial area in diabetic rats, whereas ACE inhibitor treatment had an incomplete effect. It can be concluded that in the streptozotocin model, hyperglycemia is followed by an early macrophage recruitment that contributes to the molecular and structural events that could lead to glomerulosclerosis. Therefore, besides direct stimulation of mesangial cells by hyperglycemia, macrophages recruited in the glomeruli during the early phase of hyperglycemia could secondarily act on mesangial cells.
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              Reactive oxygen species, cell signaling, and cell injury

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