Hsp90β is involved in the development of high salt-diet-induced nephropathy via interaction with various signalling proteins

• Published in: Open biology Vol. 6; no. 4; p. 150159
• Main Authors: Yan, Shi-hai, Zhao, Ning-wei, Jiang, Wei-min, Wang, Xin-tong, Zhang, Si-qi, Zhu, Xuan-xuan, Zhang, Chun-bing, Gao, Yan-hong, Gao, Feng, Liu, Fu-ming, Fang, Zhu-yuan
• Format: Journal Article
• Language: English
• Published: England The Royal Society 01.04.2016
• Subjects: Animals; Apoptosis - drug effects; Benzoquinones - pharmacology; Biomarkers - metabolism; Blood Pressure - drug effects; Gene Knockdown Techniques; High Salt-Diet-Induced Nephropathy; HSP90 Heat-Shock Proteins - metabolism; Hsp90β; Kidney Diseases - chemically induced; Kidney Diseases - complications; Kidney Diseases - metabolism; Kidney Diseases - physiopathology; Kidney Tubules - drug effects; Kidney Tubules - pathology; Lactams, Macrocyclic - pharmacology; Male; Models, Biological; Oxidative Stress - drug effects; Protein Binding - drug effects; Proteinuria - complications; Proteinuria - physiopathology; Proteome - metabolism; Proteomics; Rats, Inbred SHR; Rats, Inbred WKY; Shr; Signal Transduction - drug effects; Sodium Chloride, Dietary; Wky; high salt-diet-induced nephropathy; Hsp90β; WKY; SHR
• ISSN: 2046-2441; 2046-2441
• DOI: 10.1098/rsob.150159

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.