Figure 11.

Schema for the effect of Klotho and Pi on senescence and fibrosis in the kidney. On the one hand, high Pi upregulates p16 and p21 expression in the kidney and induces senescence (early phase), PAI-1 upregulation, and Klotho downregulation (later phase). Whether Pi stimulates PAI-1 dependently or independently of upregulation of p16/p21 or downregulation of Klotho signaling is unclear (dash line). High PAI-1 promotes fibrin deposits in peritubular capillaries, and also activates senescence, injury and EMT in kidney tubules. On the other hand, Klotho deficiency increases plasma Pi. Senescence amplifies the number of senescent cells through activation of a vicious cycle of secreted pro-inflammatory cytokines and pro-fibrotic growth factors called SASP. As a result, elevation of senescence in kidney tubules and massive deposits of fibrin in vessels trigger or/and accelerate fibrogenesis in the kidney. Klotho could improve Pi homeostasis, attenuate the upregulation of p16/p21 and PAI-1 to decrease senescence, and alleviate kidney fibrosis.