title: Hsp90β is involved in the development of high salt-diet-induced nephropathy via interaction with various signalling proteins.
abstract: A high-salt diet often leads to a local intrarenal increase in renal hypoxia and oxidative stress, which are responsible for an excess production of pathogenic substances. Here, Wistar Kyoto/spontaneous hypertensive (WKY/SHR) rats fed a high-salt diet developed severe proteinuria, resulting from pronounced renal inflammation, fibrosis and tubular epithelial cell apoptosis. All these were mainly non-pressure-related effects. Hsp90β, TGF-β, HIF-1α, TNF-α, IL-6 and MCP-1 were shown to be highly expressed in response to salt loading. Next, we found that Hsp90β might play the key role in non-pressure-related effects of salt loading through a series of cellular signalling events, including the NF-κB, p38 activation and Bcl-2 inactivation. Hsp90β was previously proven to regulate the upstream mediators in multiple cellular signalling cascades through stabilizing and maintaining their activities. In our study, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) or Hsp90β knockdown dramatically alleviated the high-salt-diet-induced proteinuria and renal damage without altering blood pressure significantly, when it reversed activations of NF-κB, mTOR and p38 signalling cascades. Meanwhile, Co-IP results demonstrated that Hsp90β could interact with and stabilize TAK1, AMPKα, IKKα/β, HIF-1α and Raptor, whereas Hsp90β inhibition disrupted this process. In addition, Hsp90β inhibition-mediated renal improvements also accompanied the reduction of renal oxidative stress. In conclusion, salt loading indeed exhibited non-pressure-related impacts on proteinuria and renal dysfunction in WKY/SHR rats. Hsp90β inhibition caused the destabilization of upstream mediators in various pathogenic signalling events, thereby effectively ameliorating this nephropathy owing to renal hypoxia and oxidative stress.
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Shi-hai
authors.initials: SH
authors.lastname: Yan
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China Shimadzu Biomedical Research Laboratory, Shanghai, People's Republic of China sshznw@shimadzu.com.cn.
authors.forename: Ning-wei
authors.initials: NW
authors.lastname: Zhao
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Wei-min
authors.initials: WM
authors.lastname: Jiang
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Xin-tong
authors.initials: XT
authors.lastname: Wang
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Si-qi
authors.initials: SQ
authors.lastname: Zhang
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Xuan-xuan
authors.initials: XX
authors.lastname: Zhu
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Chun-bing
authors.initials: CB
authors.lastname: Zhang
authors.affiliation: Nanjing Normal University, Nanjing, People's Republic of China.
authors.forename: Yan-hong
authors.initials: YH
authors.lastname: Gao
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China.
authors.forename: Fu-ming
authors.initials: FM
authors.lastname: Liu
authors.affiliation: Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, People's Republic of China zhuyuan600@sina.cn.
authors.forename: Zhu-yuan
authors.initials: ZY
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011507:Proteinuria / Q000150:complications / Q000503:physiopathology; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D017673:Sodium Chloride, Dietary
chemical_list: D016227:Benzoquinones; D015415:Biomarkers; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D020543:Proteome; D017673:Sodium Chloride, Dietary; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
keywords: Hsp90β; SHR; WKY; high salt-diet-induced nephropathy