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      Combined Blockade of Smad3 and JNK Pathways Ameliorates Progressive Fibrosis in Folic Acid Nephropathy

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          Abstract

          Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signaling pathways promote interstitial fibrosis; however, effective suppression of fibrosis may require blockade of more than one pathway. This study investigated whether blockade of Smad3 and c-Jun N-terminal kinase (JNK) signaling gives added suppression of interstitial fibrosis in folic acid nephropathy. A single high dose of folic acid (FA) causes acute tubular damage in C57BL/6J mice followed by interstitial fibrosis and chronic renal impairment. Co-activations of Smad3 and JNK signaling occur in both tubular epithelial cells and myofibroblasts in areas of tubulointerstitial damage and fibrosis in both murine FA-induced nephropathy and human IgA nephropathy. Groups of mice were treated with a Smad3 inhibitor (SIS3), a JNK inhibitor (SP600125), or a combination from day 6 after FA administration until being killed on day 28. Each drug efficiently inhibited its specific target (Smad3 phosphorylation or c–Jun phosphorylation) without affecting the other pathway. Given alone, each drug partially reduced renal fibrosis, whereas the combination therapy gave an additive and profound protection from renal fibrosis and improved renal function. Inhibition of Smad3 and/or JNK signaling activities prevented down-regulation of PGC-1α in tubular epithelial cells and up-regulation of PGC-1α in myofibroblasts during FA-induced renal fibrosis and inflammation. The expression of PGC-1α was upregulated in Smad3 −/− NRK52E cells while downregulated in Smad3 −/− NRK49F cells, suggesting that Smad3 signaling may regulate expression of PGC-1α in renal tubular epithelial cells and fibroblasts in distinct fashion. In vivo and cell culture studies also indicate that Smad3 and JNK signaling cooperate to cause mitochondrial dysfunction and cell damage in tubular epithelial cells via direct actions on the transcription of PGC-1α. These pathways also act cooperatively to promote renal fibroblast proliferation in tempo-spatial fashion. In conclusion, we have identified a potential combination therapy for progressive renal fibrosis which operates, in part, through modifying mitochondrial function.

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          Most cited references30

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          Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.

          We report here the purification and cDNA cloning of Apaf-1, a novel 130 kd protein from HeLa cell cytosol that participates in the cytochrome c-dependent activation of caspase-3. The NH2-terminal 85 amino acids of Apaf-1 show 21% identity and 53% similarity to the NH2-terminal prodomain of the Caenorhabditis elegans caspase, CED-3. This is followed by 320 amino acids that show 22% identity and 48% similarity to CED-4, a protein that is believed to initiate apoptosis in C. elegans. The COOH-terminal region of Apaf-1 comprises multiple WD repeats, which are proposed to mediate protein-protein interactions. Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis.
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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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              An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle.

              Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). Transgenic expression of PGC-1alpha recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1alpha expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1alpha largely through the binding of cAMP response element-binding protein to the PGC-1alpha promoter. Moreover, we show that a positive feedback loop exists between PGC-1alpha and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1alpha promoter and activate it, predominantly when coactivated by PGC-1alpha. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1alpha. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1alpha, contributing to the relatively stable nature of muscle fiber-type determination.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                09 August 2019
                2019
                : 10
                : 880
                Affiliations
                [1] 1Department of Pediatrics, the First Affiliated Hospital, Sun Yat-sen University , Guangzhou, China
                [2] 2Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University , Clayton, VIC, Australia
                [3] 3Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University , Guangzhou, China
                [4] 4Key Laboratory of Nephrology, National Health Commission and Guangdong Province , Guangzhou, China
                [5] 5Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organisation (CSIRO) , Melbourne, VIC, Australia
                [6] 6Australian Regenerative Medicine Institute, Monash University , Clayton, VIC, Australia
                [7] 7Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC, Australia
                [8] 8Institute of Nephrology, Zhong Da Hospital, Southeast University , Nanjing, China
                [9] 9Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University , Nanjing, China
                [10] 10Florida State University College of Medicine , Tallahassee, FL, United States
                [11] 11Department of Nephrology, Monash Health and Monash University Department of Medicine , Clayton, VIC, Australia
                [12] 12The Second Clinical College and Shunde Women and Children Hospital, Guangdong Medical University , Shunde, China
                [13] 13Guangdong Academy of Medical Science, Guangdong Provincial People’s Hospital , Guangzhou, China
                Author notes

                Edited by: Xueying Zhao, Morehouse School of Medicine, United States

                Reviewed by: Isha Sharma, Northwestern University, United States; Zhengrong Guan, University of Alabama at Birmingham, United States

                *Correspondence: Jinhua Li, jinhua.li@ 123456monash.edu ; Xiaoyun Jiang, xyjiang-3208@ 123456163.com ; Xueqing Yu, yuxq@ 123456mail.sysu.edu.cn

                This article was submitted to Renal Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.00880
                6695473
                31447676
                f725d740-af7d-495b-97d6-2a8a4b7fb34d
                Copyright © 2019 Jiang, Fan, Qu, Li, Nilsson, Sun, Chen, Yu, Liu, Liu, Tang, Chen, Ren, Nikolic-Paterson, Jiang, Li and Yu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 May 2019
                : 10 July 2019
                Page count
                Figures: 10, Tables: 0, Equations: 0, References: 39, Pages: 17, Words: 6636
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                tubulointerstitial fibrosis,smad3,jnk1/2,pgc-1α,mitochondrial dysfunction

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