Soluble αKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1α 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 αKlotho 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 αKlotho 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 Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification in response to CKD. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1, which abolished Hsp90aa1-Hif1α 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.