In the present study, we found that LIPUS treatment effectively alleviated the upregulation of CHOP, Bax, and cleaved caspase-3 protein levels and the downregulation of Bcl-2 protein level in NRK-52E cells during H/R challenge and in the kidneys of IRI-AKI mice, indicating LIPUS treatment protects renal cells from IRI via inhibiting CHOP signaling and increasing Bcl-2/Bax ratio pathways. The gene discussed is DDIT3; the disease is acute kidney injury.