Although it is previously reported that Klotho serves as an endogenous antagonist of Wnt/β‐catenin signaling (Kadoya et al., 2020; Zhou et al., 2013), protects mitochondrial function in aged cells (Miao et al., 2019; Sahu et al., 2018), and Klotho protects against renal fibrosis (Zhou, Mo, et al., 2015), the present study shows for the first time that Klotho strongly inhibit tubular cellular senescence and protects mitochondrial function in CKD mouse model. Here, KL is linked to renal fibrosis.