Soluble aKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1a stabilization and alleviate CKD-induced vascular calcification
Vascular calcification is the major risk factor for increased cardiovascular morbidity and mortality in patients with CKD, especially those with advanced renal diseases. However, once mineral deposits form in vascular tissue, no specific therapies can completely arrest or reverse the progression of calcification. Here, we identified that decreased serum soluble aKlotho levels are characteristic events in the development of vascular calcification in patients with early CKD. We employed a transcriptomicsapproach, as well as in vitro and in vivo vascular calcification models, and determined that soluble aKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1a, thereby playing a causative role in the pathogenesis of vascular calcification in response to CKD. Upregulation of soluble aKlotho expression in VSMCs enhanced the interaction with Hsp90aa1, which abolished Hsp90aa1-Hif1a axis activation in response to osteogenic induction. Together, these results identify a key pathway in VSMCs that mediates vascular calcification, which could be used as a potential therapeutic target. Overall design: Comparative gene expression profiling analysis of RNA-seq data for MA-VSMCs after treatment with calcification medium or without it, combined with or without aKlotho lentiviral vector transfection