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      Polydatin impairs mitochondria fitness and ameliorates podocyte injury by suppressing Drp1 expression

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          Abstract

          Polydatin (PD), a resveratrol glycoside, has been shown to protect renal function in diabetic nephropathy (DN), but the underlying molecular mechanism remains unclear. This study demonstrates that PD stabilize the mitochondrial morphology and attenuate mitochondrial malfunction in both KKAy mice and in hyperglycemia (HG)‐induced MPC5 cells. We use Western blot analysis to demonstrate that PD reversed podocyte apoptosis induced by HG via suppressing dynamin‐related protein 1 (Drp1). This effect may depend on the ability of PD to inhibit the generation of cellular reactive oxygen species (ROS). In conclusion, we demonstrate that PD may be therapeutically useful in DN, and that, podocyte apoptosis induced by HG can be reversed by PD through suppressing Drp1 expression.

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          Most cited references 30

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          A new method for large scale isolation of kidney glomeruli from mice.

          Here we report a new isolation method for mouse glomeruli. The method is fast and simple and allows for the isolation of virtually all glomeruli present in the adult mouse kidney with minimal contamination of nonglomerular cells. Mice were perfused through the heart with magnetic 4.5- micro m diameter Dynabeads. Kidneys were minced into small pieces, digested by collagenase, filtered, and collected using a magnet. The number of glomeruli retrieved from one adult mouse was 20,131 +/- 4699 (mean +/- SD, n = 14) with a purity of 97.5 +/- 1.7%. The isolated glomeruli retained intact morphology, as confirmed by light and electron microscopy, as well as intact mRNA integrity, as confirmed by Northern blot analysis. The method was applicable also to newborn mice, which allows for the isolation of immature developmental stage glomeruli. This method makes feasible transcript profiling and proteomic analysis of the developing, healthy and diseased mouse glomerulus.
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            Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.

            Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.
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              Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency.

              Coenzyme Q(10) (CoQ(10)) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. The relative importance of respiratory chain defects, ROS production, and apoptosis in the pathogenesis of CoQ(10) deficiency is unknown. We determined previously that severe CoQ(10) deficiency in cultured skin fibroblasts harboring COQ2 and PDSS2 mutations produces divergent alterations of bioenergetics and oxidative stress. Here, to better understand the pathogenesis of CoQ(10) deficiency, we have characterized the effects of varying severities of CoQ(10) deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ(10) biosynthesis. Levels of CoQ(10) seem to correlate with ROS production; 10-15% and >60% residual CoQ(10) are not associated with significant ROS production, whereas 30-50% residual CoQ(10) is accompanied by increased ROS production and cell death. Our results confirm that varying degrees of CoQ(10) deficiency cause variable defects of ATP synthesis and oxidative stress. These findings may lead to more rational therapeutic strategies for CoQ(10) deficiency.
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                Author and article information

                Contributors
                1125526381@qq.com
                qiujingwang@163.com
                xinli268@gmail.com
                Journal
                J Cell Physiol
                J. Cell. Physiol
                10.1002/(ISSN)1097-4652
                JCP
                Journal of Cellular Physiology
                John Wiley and Sons Inc. (Hoboken )
                0021-9541
                1097-4652
                27 April 2017
                October 2017
                : 232
                : 10 ( doiID: 10.1002/jcp.v232.10 )
                : 2776-2787
                Affiliations
                [ 1 ] Shenzhen Hospital of Southern Medical University Shenzhen Guangdong PR China
                [ 2 ] College of Stomatology of Guangxi Medical University Nanning Guangxi PR China
                [ 3 ] Pharmaceutical College Guangxi Medical University Nanning Guangxi PR China
                [ 4 ] Department of Neurosurgery, Zhujiang Hospital Southern Medical University Guangdong Province China
                Author notes
                [* ] Correspondence

                Zheng Ni, Shenzhen Hospital of Southern Medical university, Central laboratory; No.1333, Xinhu Road, Shenzhen 518104, PR China.

                Email: 1125526381@ 123456qq.com

                Wang Qiujing, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253# industry road, Guangzhou, 510282, Guangdong Province, PR China.

                Email: qiujingwang@ 123456163.com

                Li Xin, Shenzhen Hospital of Southern Medical university, Central laboratory;

                No.1333, Xinhu Road, Shenzhen 518104, PR China.

                Email: xinli268@ 123456gmail.com

                Article
                JCP25943
                10.1002/jcp.25943
                5518182
                28383775
                © 2017 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 8, Tables: 2, Pages: 12, Words: 6808
                Product
                Funding
                Funded by: Education Innovation Plan Program for Postgraduate in Guangxi Zhuang Autonomous Region
                Award ID: 2011105981002D27
                Funded by: Natural Science Foundation of Guangxi Province
                Award ID: 2012‐181h‐02 2012GXNSFAA053106
                Award ID: 0832013Z
                Funded by: National Natural Science Foundation of China
                Award ID: 81160533
                Award ID: 8150040851
                Categories
                Original Research Article
                Original Research Articles
                Custom metadata
                2.0
                jcp25943
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:20.07.2017

                Anatomy & Physiology

                diabetic nephropathy, dynamin‐related protein 1, polydatin

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