Figure 11.

Interplay of Klotho, phosphate, and vascular endothelial growth factor receptor type 2 (VEGFR2) in the peritubular vasculature and kidney fibrosis. A: high dietary phosphate loading induces cell damage. Damaged endothelial cells 1) dedifferentiate to fibroblasts through endothelial mesenchymal transition and 2) reduce VEGFR2 expression and consequently downregulate VEGFR2 signaling activity. On the other hand, VEGFR2 deficiency inhibits VEGFR2 signaling activity, which renders cells more vulnerable to phosphotoxicity. Low VEGFR2 signaling activity causes peritubular vascular loss. Peritubular capillary rarefaction induces kidney tubular ischemia and damage as well as tubulointerstitial fibrosis. Klotho deficiency suppresses VEGFR2 activity and exacerbates phosphotoxicity-induced endothelial injury. B: elevation of soluble Klotho through Klotho supplementation increases VEGFR2 signaling activity and attenuates phosphotoxicity on endothelial cells, thus improving vasculogenesis and angiogenesis and reducing endothelial-mesenchymal transition. Soluble Klotho also promotes peritubular capillary regeneration and reduces kidney fibrosis through a VEGFR2-independent pathway. Taken together, the peritubular capillary is preserved, and kidney fibrosis is attenuated.