Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to...

Area of Science:

• Vascular Biology and Medicine
• Endocrinology and Metabolism

Background:

• Fibroblast growth factor (FGF)-23 is crucial for kidney function, but its role in chronic kidney disease (CKD) vascular calcification is debated.
• Klotho acts as a cofactor for FGF-23, and its levels are altered in CKD.

Purpose of the Study:

• To investigate endogenous Klotho expression in human arteries and its role in CKD-associated vascular calcification.
• To determine if vitamin D receptor activators can restore vascular Klotho and influence FGF-23 effects.

Main Methods:

• Examined endogenous Klotho expression in human arteries and aortic smooth muscle cells.
• Utilized Klotho knockdown models to study calcification pathways (Runx2, myocardin-serum response factor).
• Investigated FGF-23 signaling (p-ERK, p-AKT) and effects of vitamin D receptor activators in vitro and in vivo using human arterial organ cultures.

Main Results:

• CKD is associated with vascular Klotho deficiency, promoting calcification via Runx2 and myocardin-serum response factor.
• Vascular cells are Klotho-dependent targets for FGF-23; FGF-23 effects on ERK/AKT signaling and proliferation are abrogated by Klotho knockdown.
• Vitamin D receptor activators restored vascular Klotho expression, making cells responsive to FGF-23 and revealing potential anticalcific effects.

Conclusions:

• Vascular Klotho deficiency, driven by CKD-related stress, promotes vascular calcification.
• Vascular Klotho acts as an endogenous calcification inhibitor and is essential for FGF-23 signaling.
• Vitamin D receptor activators can restore Klotho expression and FGF-23's protective vascular effects in CKD.