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Updated: Sep 16, 2025
Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
Published on: July 21, 2021
Soluble αKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1α stabilization and alleviate
Fengyang Xu1, Jialin Guo1, Yunyun Guo1
1Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China; Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, China; National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.
Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.
Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.
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