Exercise reduces hyperlipidemia-induced kidney damage in apolipoprotein E-deficient mice

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Abstract

Hyperlipidemia is a risk factor of kidney damage that can lead to chronic kidney disease. Studies have shown that exercise reduces kidney damage; however, the specific mechanisms underlying the protective effects of exercise remain unclear. For 12 weeks, 8-week-old male apolipoprotein E-deficient (ApoE ^-/-) mice were randomly divided into four treatment groups (n=7/group) as follows: Mice fed a normal diet (ND group); mice fed a ND and exercised (ND + E group); mice fed a high-fat diet (HD group); and mice fed a HD and exercised (HD + E group). Exercise training consisted of swimming for 40 min, 5 days/week. Metabolic parameters, such as low-density lipoprotein-cholesterol, total cholesterol and creatinine levels were higher in the ApoE ^-/- HD mice compared with those in the ApoE ^-/- HD + E mice. Serum levels of glutathione peroxidase and superoxide dismutase were significantly decreased in the HD group compared with those in the HD + E group. Significant pathological changes were observed in the HD + E group compared with in the HD group. Immunohistochemistry and immunoblotting revealed increased levels of oxidative stress (nuclear factor erythroid-2-related factor 2) and fibrosis (Smad3 and TGF-β) markers in the ApoE ^-/- HD group; however, the expression levels of these markers were significantly decreased in the ApoE ^-/- HD + E group. Furthermore, NF-κB expression in the HD + E group was significantly lower compared with that in the HD group. These results suggested that exercise may exert protective effects against kidney damage caused by hyperlipidemia.

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TGF-β: the master regulator of fibrosis.

Xiao-ming Meng, David J Nikolic-Paterson, Hui-Yao Lan (2016)

Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.

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Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Agnieszka Loboda, Milena Damulewicz, Elżbieta Pyza … (2016)

The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

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NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma.

Tom Luedde, Robert Schwabe (2011)

Hepatic cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of death in patients with chronic liver disease. Chronic liver injury of virtually any etiology triggers inflammatory and wound-healing responses that in the long run promote the development of hepatic fibrosis and HCC. Here, we review the role of the transcription factor nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death, in the development of hepatocellular injury, liver fibrosis and HCC, with a particular focus on the role of NF-κB in different cellular compartments of the liver. We propose that NF-κB acts as a central link between hepatic injury, fibrosis and HCC, and that it may represent a target for the prevention or treatment of liver fibrosis and HCC. However, NF-κB acts as a two-edged sword and inhibition of NF-κB may not only exert beneficial effects but also negatively impact hepatocyte viability, especially when NF-κB inhibition is pronounced. Finding appropriate targets or identifying drugs that either exert only a moderate effect on NF-κB activity or that can be specifically delivered to nonparenchymal cells will be essential to avoid the increase in liver injury associated with complete NF-κB blockade in hepatocytes.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): February 2021

Publication date (Electronic): 17 December 2020

Publication date PMC-release: 17 December 2020

Volume: 21

Issue: 2

Electronic Location Identifier: 153

Affiliations

[1 ]Department of Cardiology, Zhejiang Province Rongjun Hospital, Jiaxing, Zhejiang 314000, P.R. China

[2 ]Department of Internal Medicine, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China

[3 ]Department of Cardiology, Dalian Third People's Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116200, P.R. China

[4 ]Department of Heart Intensive Care Unit, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China

Author notes

Correspondence to: Professor Yan Sun, Department of Cardiology, Zhejiang Province Rongjun Hospital, 309 Shuangyuan Road, Jiaxing, Zheijiang 314000, P.R. China 1579938913@ 123456qq.com

Professor Hongyang Liu, Department of Heart Intensive Care Unit, The First Affiliated Hospital of Dalian Medical University, 193 Lianhe Road, Dalian, Liaoning 116011, P.R. China Yang060188@ 123456163.com

Abbreviations: ApoE ^-/-, apolipoprotein E-deficient; LDL-c low-density lipoprotein-cholesterol; TC, total cholesterol; CRE, creatinine; GSH-PX, glutathione peroxidase; SOD, superoxide dismutase; CKD, chronic kidney disease; PAS, Periodic acid-Schiff; IHC, immunohistochemistry; NRF2, nuclear factor erythroid-2-related factor 2

Article

Publisher ID: ETM-0-0-09585

DOI: 10.3892/etm.2020.9585

PMC ID: 7792504

PubMed ID: 33456520

SO-VID: 63699d4d-06cd-47ba-ae1d-2ba5605206fa

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Exercise reduces hyperlipidemia-induced kidney damage in apolipoprotein E-deficient mice

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Most cited references 39

TGF-β: the master regulator of fibrosis.

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma.

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