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      Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis

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          Kidney disease associated with diabetes mellitus is a major health problem worldwide. Although established therapeutic strategies, such as appropriate blood glucose control, blood pressure control with renin–angiotensin system blockade, and lipid lowering with statins, are used to treat diabetes, the contribution of diabetic end-stage kidney disease to the total number of cases requiring hemodialysis has increased tremendously in the past two decades. Once renal function starts declining, it can result in a higher frequency of renal and extra-renal events, including cardiovascular events. Therefore, slowing renal function decline is one of the main areas of focus in diabetic nephropathy research, and novel strategies are urgently needed to prevent diabetic kidney disease progression. Regardless of the type of injury and etiology, kidney fibrosis is the commonly the final outcome of progressive kidney diseases, and it results in significant destruction of normal kidney structure and accompanying functional deterioration. Kidney fibrosis is caused by prolonged injury and dysregulation of the normal wound-healing process in association with excess extracellular matrix deposition. Kidney fibroblasts play an important role in the fibrotic process, but the origin of the fibroblasts remains elusive. In addition to the activation of residential fibroblasts, other important sources of fibroblasts have been proposed, such as pericytes, fibrocytes, and fibroblasts originating from epithelial-to-mesenchymal and endothelial-to-mesenchymal transition. Inflammatory cells and cytokines play a vital role In the process of fibroblast activation. In this review, we will analyze the contribution of inflammation to the process of tissue fibrosis, the type of fibroblast activation and the therapeutic strategies targeting the inflammatory pathways in an effort to slow the progression of diabetic kidney disease.

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          Most cited references 149

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          Transforming growth factor beta in tissue fibrosis.

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            Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.

             Thomas Wynn (2007)
            Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.
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              BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

              Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrin.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                06 February 2013
                : 4
                1Division of Diabetology and Endocrinology, Kanazawa Medical University Kahoku, Japan
                2Department of Nephrology, Nizam’s Institute of Medical Sciences Hyderabad, India
                Author notes

                Edited by: Gabriel Virella, Universidade de Lisboa, Portugal

                Reviewed by: Subrata Chakrabarti, The University of Western Ontario, Canada; Undurti Narasimha Das, UND Life Sciences, USA

                *Correspondence: Keizo Kanasaki and Daisuke Koya, Division of Diabetology and Endocrinology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku Ishikawa 920-0293, Japan. e-mail: kkanasak@ ; koya0516@ ; Gangadhar Taduri, Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad 500082, Andhra Pradesh, India. e-mail: gangadhar3@

                This article was submitted to Frontiers in Diabetes, a specialty of Frontiers in Endocrinology.

                Copyright © Kanasaki, Taduri and Koya.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 192, Pages: 15, Words: 0
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