Activation of peroxisome proliferator-activated receptor γ inhibits vascular calcification by upregulating Klotho

Cardiovascular diseases are common in patients with chronic kidney disease. One of the key symptoms is the calcification of the vascular smooth muscle cells (VSMCs), which is induced by dysregulated mineral metabolism with high circulating levels of inorganic phosphate (Pi) and calcium. Klotho, which was originally identified as an aging suppressor gene, has been shown to be associated with vascular calcification. Since Klotho was recently identified as a target for nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, the present study aimed to determine whether PPAR gamma regulates VSMC calcification through modulating the expression levels of Klotho. It was demonstrated that the expression of PPAR gamma was downregulated during Pi-induced VSMC calcification. In addition, treatment with PPAR gamma agonists inhibited the calcification and enhanced the expression of Klotho in VSMCs in a PPAR gamma-dependent manner. Of note, loss of Klotho expression by RNA interference abolished the ability of PPAR gamma activation to inhibit VSMC calcification. Furthermore, activation of Klotho as well as PPAR gamma inhibited the expression of Pi transporter 1/2 and reduced Pi influx into VSMCs. To the best of our knowledge, the present study was the first to demonstrate that PPAR gamma regulates VSMC calcification through activating Klotho.