Lipolysis-stimulated lipoprotein receptor (LSR) is a single-pass membrane protein which plays essential roles in tricellular tight junction organization in epithelium and endothelium, but its function in kidney physiology and disease development remains unknown. Conditional Lsr deletion mice were generated and analyzed to investigate function of LSR in proximal tubule. Unilateral ischemia-reperfusion was used as injury model to investigate the role of LSR in acute kidney injury (AKI) and the progression to chronic kidney disease (CKD). Detailed mechanistic analyses were conducted using whole-transcriptome RNA sequencing, immunofluorescence, dual-luciferase reporter gene assay, coimmunoprecipitation, RNA immunoprecipitation, and adeno-associated virus-mediated gene overexpression and knockdown. The nuclear localization of LSR was found in the kidney. Proximal tubule-specific Lsr knockout mice exhibited alleviated kidney damage and fibrosis than those in wildtype mice in response unilateral ischemia-reperfusion injury. Loss of LSR resulted in downregulation of Chrdl1 and activation of BMP-SMAD signaling in proximal tubules. Treatment with CHRDL1 counteracted the protective effect of LSR deletion in the unilaterally ischemic injured kidney. Additionally, systemic delivery of Chrdl1 shRNA attenuated injury-induced kidney fibrosis. LSR formed a complex with 14-3-3θ in the nucleus of proximal tubular cells, thereby reducing the interaction between human antigen R and 14-3-3θ, consequently leading to the translocation of unbound human antigen R to the cytoplasm. The absence of LSR promoted the association of 14-3-3θ with human antigen R, potentially resulting in decreased human antigen R levels in the cytoplasm. Reduced human antigen R levels impaired Chrdl1 mRNA stability, subsequently leading to the activation of BMP-SMAD signaling. Deletion of LSR in proximal tubule deregulated Chrdl1 to activate BMP-SMAD signaling and ameliorated kidney disease.