Lipolysis-Stimulated Lipoprotein Receptor in Proximal Tubule, BMP-SMAD Signaling, and Kidney Disease

Key Points We identify that lipolysis-stimulated lipoprotein receptor is highly enriched in the nucleus of mouse and human kidney. This study provides new insights into the role of lipolysis-stimulated lipoprotein receptor in kidney disease. Background Lipolysis-stimulated lipoprotein receptor (LSR) is a single-pass membrane protein that plays essential roles in tricellular tight junction organization in the epithelium and endothelium, but its function in kidney physiology and disease development remains unknown. Methods Conditional Lsr deletion mice were generated and analyzed to investigate the function of LSR in proximal tubule. Unilateral ischemia-reperfusion was used as an injury model to investigate the role of LSR in AKI and the progression to 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. Results The nuclear localization of LSR was found in the kidney. Proximal tubule–specific Lsr knockout mice exhibited alleviated kidney damage and fibrosis compared with those in wild-type mice in response unilateral ischemia-reperfusion injury. Loss of LSR resulted in downregulation of Chrdl1 and activation of bone morphogenetic protein (BMP)-mothers against decapentaplegic homolog (SMAD) signaling in proximal tubules. Treatment with CHRDL1 counteracted the protective effect of LSR deletion in the unilaterally ischemic injured kidney. In addition, the systemic delivery of Chrdl1 short hairpin RNA 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. Conclusions Deletion of LSR in proximal tubule deregulated Chrdl1 to activate BMP-SMAD signaling and ameliorated kidney disease.