Aim: This study aimed to investigate the effect and mechanism of Klotho in lipopolysaccharide (LPS)-induced inflammation injury in HK-2 cells. Methods: We established LPS-induced inflammation injury model in HK-2 cells. The LPS-induced HK-2 cells were transfected with pc-Klotho, pcDNA3.1, siKlotho or siNC. Cell viability, apoptosis and reactive oxygen species (ROS) level were detected by MIT assay, Annexin V-FITC/PI Apoptosis Detection kit and 2,7-dichlorofluorescein diacetate, respectively. The levels of inflammatory factors and the expressions of proteins related to Wnt and nuclear factor-KB (NF-KB) signaling pathway were detected by RT-qPCR and western blotting, respectively. Results: Compared with cells transfected with pcDNA 3.1, cell viability was remarkably increased and cell apoptosis rate was decreased in LPS-induced cells with pc-Klotho (p < 0.05). Conversely, LPS-induced cells with siKlotho showed lower cell viability and higher cell apoptosis rate than cells with siNC (p < 0.05). The levels of ROS, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) was significantly reduced in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05). Consistently, LPS-induced cells with siKlotho showed increased levels of ROS, TNF-a and IL-6 compared with cells with siNC (p < 0.05). Wnt signaling pathway related protein Wnt3a and NF-KB signaling pathway related to proteins p-IKBa were significantly down-regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1, while up-regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05). Conclusions: Klotho may play an inhibiting role in LPS-induced inflammation injury by inhibiting NF-KB and Wnt signaling pathways in HK-2 cells.