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      C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

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          Abstract

          C-reactive protein (CRP) is associated with progressive diabetic nephropathy in patients with type-2 diabetes (T2DN). However, role of CRP in T2DN remains unclear. We report here that CRP is pathogenic in T2DN in db/db mice that express human CRP (CRPtg-db/db). Compared to the littermate db/db mice, CRPtg-db/db developed more severe T2DN, showing higher levels of fasting blood glucose and microalbuminuria and more progressive renal inflammation and fibrosis. Enhanced T2DN in CRPtg-db/db mice were associated with over-activation of CRP-CD32b, NF-κB, TGF-β/Smad3, and mTOR signaling. Further studies in vitro defined that CRP activated Smad3 directly at 15 mins via the CD32b- ERK/p38 MAP kinase crosstalk pathway and indirectly at 24 hours through a TGF-β1-dependent mechanism. Importantly, CRP also activated mTOR signaling at 30 mins via a Smad3-dependent mechanism as Smad3 bound mTOR physically and CRP-induced mTOR signaling was abolished by a neutralizing CD32b antibody and a specific Smad3 inhibitor. Finally, we also found that CRP induced renal fibrosis through a CD32b-Smad3-mTOR pathway because blocking mTOR signaling with rapamycin inhibited CRP-induced CTGF and collagen I expression. Thus, CRP is pathogenic in T2DN. CRP may promote CD32b- NF-κB signaling to mediate renal inflammation; whereas, CRP may enhance renal fibrosis in T2DN via CD32b-Smad3-mTOR signaling.

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          Most cited references36

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          Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.

          Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway

            Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-β (TGF-β) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-β induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-β of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E–binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-β–induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-β–induced EMT. The TGF-β–induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-β, which leads to increased cell size and invasion, adds to the role of TGF-β–induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.
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              Mouse models of diabetic nephropathy.

              Diabetic nephropathy is a major cause of ESRD worldwide. Despite its prevalence, a lack of reliable animal models that mimic human disease has delayed the identification of specific factors that cause or predict diabetic nephropathy. The Animal Models of Diabetic Complications Consortium (AMDCC) was created in 2001 by the National Institutes of Health to develop and characterize models of diabetic nephropathy and other complications. This interim report and our online supplement detail the progress made toward that goal, specifically in the development and testing of murine models. Updates are provided on validation criteria for early and advanced diabetic nephropathy, phenotyping methods, the effect of background strain on nephropathy, current best models of diabetic nephropathy, negative models, and views of future directions. AMDCC investigators and other investigators in the field have yet to validate a complete murine model of human diabetic kidney disease. Nonetheless, the critical analysis of existing murine models substantially enhances our understanding of this disease process.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                25 May 2016
                2016
                : 6
                : 26740
                Affiliations
                [1 ]Institute of Nephrology, Guangdong Medical College , Zhanjiang, Guangdong, China
                [2 ]Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong , Hong Kong, China
                Author notes
                Article
                srep26740
                10.1038/srep26740
                4879671
                27221338
                91d7a27b-a140-4ae7-a559-0b9bca5f8e43
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 05 April 2016
                : 06 May 2016
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