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      Silibinin Augments the Antifibrotic Effect of Valsartan Through Inactivation of TGF-β1 Signaling in Kidney

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          Chronic kidney disease (CKD) has become a major public health issue. Meanwhile, renal fibrosis caused by diabetic nephropathy can lead to CKD, regardless of the initial injury. It has been previously reported that silibinin or valsartan could relieve the severity of renal fibrosis. However, the effect of silibinin in combination with valsartan on renal fibrosis remains unclear.

          Material and Methods

          Proximal tubular cells (HK-2) were treated with TGF-β1 (5 ng/mL) to mimic in vitro model of fibrosis. The proliferation of HK-2 cells was tested by CCK-8. Epithelial-mesenchymal transition (EMT) and inflammation-related gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of TNF- αNF-A. Additionally, HFD-induced renal fibrosis mice model was established to investigate the effect of silibinin in combination with valsartan on renal fibrosis in vivo.


          Silibinin significantly increased the anti-fibrosis effect of valsartan in TGF-β1-treated HK-2 cells via inhibition of TGF-β1 signaling pathway. Furthermore, silibinin significantly enhanced the anti-fibrosis effect of valsartan on HFD-induced renal fibrosis in vivo through inactivation of TGF-β1 signaling pathway.


          These data indicated that silibinin markedly increased anti-fibrosis effect of valsartan in vitro and in vivo. Thus, silibinin in combination with valsartan may act as a potential novel strategy to treat renal fibrosis caused by diabetic nephropathy.

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          Most cited references 33

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          The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis.

          Renal fibrosis is a common characteristic of chronic kidney disease (CKD). Aberrant and excessive depositions of extracellular matrix (ECM) proteins in both glomeruli and interstitial regions are typical hallmarks of renal fibrosis and amplify the severity of kidney injury. To date, an approved therapy specifically targeted to renal fibrosis is needed to mitigate or even retard renal fibrosis. Recent findings have identified a unique population of myofibroblasts as a primary source of ECM in scar tissue formation. However, the origin of myofibroblasts in renal fibrosis remains the subject of controversial debates. The advancement in lineage tracing and immunofluorescent microscopy technologies have suggested that myofibroblasts may arise from a number of sources such as activated renal fibroblasts, pericytes, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndoMT), bone marrow derived cells and fibrocytes. Recent studies also indicate that multiple ligands of TGF-β/Smads are the direct mediators for renal fibrosis. Consistently, inhibition of the TGF-β/Smads signaling pathway using various strategies significantly reduce renal fibrotic lesions and ameliorate kidney injury, suggesting that targeting the TGF-β/Smads signaling pathway could be a new strategy for effective therapies. In this review, we will briefly discuss the diverse origins of myofibroblasts and molecular pathways triggering renal fibrosis. Prospective therapeutic approaches based on those molecular mechanisms will hopefully offer exciting insights in the development of new therapeutic interventions for patients in the near future.
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            TGF-β1 Signaling and Tissue Fibrosis

            Activation of TGF-β1 initiates a program of temporary collagen accumulation important to wound repair in many organs. However, the outcome of temporary extracellular matrix strengthening all too frequently morphs into progressive fibrosis, contributing to morbidity and mortality worldwide. To avoid this maladaptive outcome, TGF-β1 signaling is regulated at numerous levels and intimately connected to feedback signals that limit accumulation. Here, we examine the current understanding of the core functions of TGF-β1 in promoting collagen accumulation, parallel pathways that promote physiological repair, and pathological triggers that tip the balance toward progressive fibrosis. Implicit in better understanding of these processes is the identification of therapeutic opportunities that will need to be further advanced to limit or reverse organ fibrosis.
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              TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

              Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                13 February 2020
                : 14
                : 603-611
                [1 ]Department of Ultrasound, The Affiliated Hospital of Qingdao University , Qingdao, Shandong 266003, People’s Republic of China
                Author notes
                Correspondence: Guijun Zhang Department of Ultrasound, The Affiliated Hospital of Qingdao University , 1677 Wutaishan Road, Huangdao District, Qingdao, Shandong266003, People’s Republic of China Email zhangguijun123@126.com
                © 2020 Liu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, References: 36, Pages: 9
                Original Research


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