Klotho promotes AMPK activity and maintains renal vascular integrity by regulating the YAP signaling pathway

Abstract

The development and formation of mammalian blood vessels are closely related to the regulation of signal transduction pathways. Klotho/AMPK and YAP/TAZ signaling pathways are closely related to angiogenesis, but the internal relationship between them is not clear. In this study, we found that Klotho heterozygous deletion mice (Klotho +/- mice) had obvious thickening of the renal vascular wall, obvious enlargement of vascular volume, and significant proliferation and pricking of vascular endothelial cells. Western blot showed that the expression levels of total YAP protein, p-YAP protein (Ser127 and Ser397), p-MOB1, MST1, LATS1, and SAV1 in renal vascular endothelial cells were significantly lower in Klotho +/- mice than in wild-type mice. Knockdown of endogenous Klotho in HUVECs accelerated their ability to divide and form vascular branches in the extracellular matrix. Meanwhile, the results of CO-IP western blot showed that the expression of LATS1 and p-LATS1 interacting with AMPK protein decreased significantly, and the ubiquitination level of YAP protein also decreased significantly in vascular endothelial cells of kidney tissue of Klotho +/- mice. Subsequently, continuous overexpression of exogenous Klotho protein in Klotho heterozygous deficient mice effectively reversed the abnormal renal vascular structure by weakening the expression of the YAP signal transduction pathway. Therefore, we confirmed that Klotho and AMPKα proteins were highly expressed in vascular endothelial cells of adult mouse tissues and organs; this resulted in a phosphorylation modification of YAP protein, closed the activity of the YAP/TAZ signal transduction pathway, and inhibited the growth and proliferation of vascular endothelial cells. When Klotho was absent, the phosphorylation modification of YAP protein by AMPKα was inhibited, resulting in the activation of the YAP/TAZ signal transduction pathway and finally inducing the excessive proliferation of vascular endothelial cells.

Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression

“…LATS1 is a core and upstream component of the Hippo pathway, which can regulate the downstream effectors, YAP1 and TAZ. 40 These observations support the hypothesis that AMPK might serve as an essential factor in the regulatory effect of HG on YAP1/TAZ function. in cancer cell autophagy and metabolism, a deeper investigation into these other pathways is needed.…”

“…In mouse renal vascular endothelial cells, large tumour suppressor 1 (LATS1) expression and p‐LATS1 interaction with the AMPK protein decreased significantly. LATS1 is a core and upstream component of the Hippo pathway, which can regulate the downstream effectors, YAP1 and TAZ 40 . These observations support the hypothesis that AMPK might serve as an essential factor in the regulatory effect of HG on YAP1/TAZ function.…”

The NDR family of kinases: essential regulators of aging

“…The mechanism involves the activation of AMPK, the downstream increase of SCRIB (Liu et al, 2020 ), Angiomiotin-like protein 1 and 2 (AMOTL1/2) and Angiomotin (AMOT) (DeRan et al, 2014 ) protein levels, which are involved in LATS1/2 stabilization and therefore AMPK-dependent YAP degradation. Furthermore, another study showed that Klotho ± mice, a widely used knockout mouse model in aging research that displays extremely short life span and premature aging (Kuro-o et al, 1997 ) display a weaker AMPK-LATS1 interaction as well as decreased AMPK-dependent phosphorylation of YAP (Luo et al, 2023 ). Although the exact mechanism has not been described yet, these data suggest that there is a direct interaction between AMPK and LATS1 which might be facilitated by the anti-aging protein Klotho.…”

AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration

“…Currently, it is known that klotho and FGF21 proteins can affect several signaling pathways although it seems that the inhibition of TGF-β signaling might be involved in tissue fibrosis (Ding et al 2019 ; Wang et al 2023a , b ). There are several investigations indicating that both the klotho and FGF21 proteins are able to activate AMPK signaling in many experimental models (Salminen et al 2017b ; Luo et al 2023 ). For instance, Luo et al ( 2023 ) demonstrated that the klotho protein stimulated AMPK signaling which subsequently promoted the phosphorylation and degradation of the YAP protein in mouse kidney.…”

“…There are several investigations indicating that both the klotho and FGF21 proteins are able to activate AMPK signaling in many experimental models (Salminen et al 2017b ; Luo et al 2023 ). For instance, Luo et al ( 2023 ) demonstrated that the klotho protein stimulated AMPK signaling which subsequently promoted the phosphorylation and degradation of the YAP protein in mouse kidney. As described above, YAP/TAZ signaling is recognized as an important fibrogenic pathway.…”