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      Astragaloside IV, a Novel Antioxidant, Prevents Glucose-Induced Podocyte Apoptosis In Vitro and In Vivo

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          Abstract

          Glucose-induced reactive oxygen species (ROS) production initiates podocyte apoptosis, which represents a novel early mechanism leading to diabetic nephropathy (DN). Here, we tested the hypothesis that Astragaloside IV(AS-IV) exerts antioxidant and antiapoptotic effects on podocytes under diabetic conditions. Apoptosis, albuminuria, ROS generation, caspase-3 activity and cleavage, as well as Bax and Bcl-2 mRNA and protein expression were measured in vitro and in vivo. Cultured podocytes were exposed to high glucose (HG) with 50, 100 and 200 µg/ml of AS-IV for 24 h. AS-IV significantly attenuated HG-induced podocyte apoptosis and ROS production. This antiapoptotic effect was associated with restoration of Bax and Bcl-2 expression, as well as inhibition of caspase-3 activation and overexpression. In streptozotocin (STZ)-induced diabetic rats, severe hyperglycemia and albuminuria were developed. Increased apoptosis, Bax expression, caspase-3 activity and cleavage while decreased Bcl-2 expression were detected in diabetic rats. However, pretreatment with AS-IV (2.5, 5, 10 mg·kg −1·d −1) for 14 weeks ameliorated podocyte apoptosis, caspase-3 activation, renal histopathology, podocyte foot process effacement, albuminuria and oxidative stress. Expression of Bax and Bcl-2 mRNA and protein in kidney cortex was partially restored by AS-IV pretreatment. These findings suggested AS-IV, a novel antioxidant, to prevent Glucose-Induced podocyte apoptosis partly through restoring the balance of Bax and Bcl-2 expression and inhibiting caspase-3 activation.

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          Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines.

          Mature podocytes are among the most complex differentiated cells and possess a highly branched array of foot processes that are essential to glomerular filtration in the kidney. Such differentiated podocytes are unable to replicate and culturing of primary podocytes results in rapid growth arrest. Therefore, conditionally immortalized mouse podocyte clones (MPC) were established, which are highly proliferative when cultured under permissive conditions. Nonpermissive conditions render the majority of MPC cells growth arrested within 6 days and induce many characteristics of differentiated podocytes. Both proliferating and differentiating MPC cells express the WT-1 protein and an ordered array of actin fibers and microtubules extends into the forming cellular processes during differentiation, reminiscent of podocyte processes in vivo. These cytoskeletal rearrangements and process formation are accompanied by the onset of synaptopodin synthesis, an actin-associated protein marking specifically differentiated podocytes. In addition, focal contacts are rearranged into an ordered pattern in differentiating MPC cells. Most importantly, electrophysiological studies demonstrate that differentiated MPC cells respond to the vasoactive peptide bradykinin by changes in intracellular calcium concentration. These results suggest a regulatory role of podocytes in glomerular filtration. Taken together, these studies establish that conditionally immortalized MPC cells retain a differentiation potential similar to podocytes in vivo. Therefore, the determinative steps of podocyte differentiation and process formation are studied for the first time using an inducible in vitro model.
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            From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy.

            Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
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              Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria.

              The predictive value of glomerular structure on progression of renal disease was examined in patients with Type II (non-insulin-dependent) diabetes and microalbuminuria (urinary albumin-to-creatinine ratio = 30-299 mg/g). Kidney biopsy specimens were obtained from 16 diabetic Pima Indians (6 men, 10 women). Progression of renal disease was assessed by measuring urinary albumin excretion 4 years after the biopsy (UAE(4 years)) and by computing the change in urinary albumin excretion during the study (Delta UAE). At baseline, the duration of diabetes averaged 13.3 years (range = 4.0-23.8 years) and the mean glomerular filtration rate was 159 ml x min(-1) x 1.73 m(-2) (range = 98 - 239 ml x min(-1) x 1.73 m(-2)). Median urinary albumin excretion was 67 mg/g (range = 25-136 mg/g) and it increased to 625 mg/g (range = 9-13471 mg/g) after 4 years; 10 subjects (63 %; 4 men, 6 women) developed macroalbuminuria (urinary albumin-to-creatinine ratio >/= 300 mg/g). Neither mean arterial pressure nor HbA(1 c) changed substantially during follow-up. Among the glomerular morphologic characteristics, the number of visceral epithelial cells, or podocytes, per glomerulus was the strongest predictor of renal disease progression (UAE(4 years), r = -0.49, p = 0.05; DeltaUAE, r = -0.57, p = 0.02), with fewer cells predicting more rapid progression. Glomerular basement membrane thickness did not predict progression (UAE(4 years), r = 0.11, p = 0.67; DeltaUAE, r = 0.09, p = 0.73) and mesangial volume fraction had only a modest effect (UAE(4 years,) r = 0.42, p = 0.11; DeltaUAE, r = 0.48, p = 0.06). Whether lower epithelial cell number per glomerulus among those that progressed was due to cellular destruction, a reduced complement of epithelial cells, or both is uncertain. Nevertheless, these findings suggest that podocytes play an important part in the development and progression of diabetic renal disease. [Diabetologia (1999) 42: 1341-1344]
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                22 June 2012
                : 7
                : 6
                : e39824
                Affiliations
                [1 ]Department of Nephrology, Zhejiang Hospital, Hangzhou, China
                [2 ]Department of Nephrology and Rheumatology, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
                [3 ]Department of Gastroenterology, No 1 Hospital of Chenzhou, Chenzhou, China
                [4 ]Institute of Integrated Chinese and Western medicine, Huashan Hospital, Fudan University, Shanghai, China
                Wayne State University, United States of America
                Author notes

                Conceived and designed the experiments: DG JH NW. Performed the experiments: DG JH FW. Analyzed the data: YG WL. Contributed reagents/materials/analysis tools: JC YC. Wrote the paper: DG JH.

                Article
                PONE-D-12-07799
                10.1371/journal.pone.0039824
                3382154
                22745830
                2cceccc9-ed25-46e0-8e4c-da1e765c226d
                Gui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 15 March 2012
                : 28 May 2012
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                Apoptotic Signaling Cascade
                Signaling in Cellular Processes
                Apoptotic Signaling
                Cellular Stress Responses
                Medicine
                Complementary and Alternative Medicine
                Drugs and Devices
                Ethnopharmacology
                Endocrinology
                Diabetic Endocrinology
                Diabetes Mellitus Type 1
                Nephrology
                Chronic Kidney Disease
                Physics
                Medical Physics

                Uncategorized
                Uncategorized

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