Targeting Podocytopathy: Liraglutide Restores Podocyte Adhesion Homeostasis via GLP1R-CD151-Dependent Integrin Signaling in FSGS

Background: Podocyte injury constitutes a critical pathogenic mechanism in glomerulopathies, with particular significance in focal segmental glomerulosclerosis (FSGS). Recent studies have demonstrated the clinical value of glucagon-like peptide-1 receptor (GLP1R) agonists in non-diabetic renal diseases, however, the exact mechanisms remain elusive. Methods: Renal biopsy samples and clinical data were collected from 12 FSGS patients to analyze the localization and expression of GLP1R and its correlation with renal injury. The protective effects of GLP1R agonist liraglutide on podocytes were examined in Adriamycin (ADR)-induced murine FSGS model. Podocyte specific GLP1R-overexpressing transgenic mice were generated to study the role of GLP1R in FSGS. In vitro, cytoskeletal organization and adhesion-related phenotypic changes were analyzed in FLAG-tagged GLP1R-overexpressing human podocyte (HPC) treated with puromycin aminonucleoside (PAN) followed by liraglutide intervention. Transcriptomic sequencing and immunoprecipitation-mass spectrometry (IP-MS) were employed. Results: The expression of GLP1R in the kidney section of FSGS patients was significantly increased mainly in the podocytes. In mice with FSGS, liraglutide intervention or podocyte-specific GLP1R overexpression significantly attenuated proteinuria and glomerular injury through a cAMP/PKA dependent pathway. In vitro, the activation of GLP1R rescued PAN-induced podocyte adhesion dysfunction through FAK/PXN pathway, restoring the expression of downstream integrin α3/β1. Mechanistically, we identified by IP-MS and Co-IP experiments that CD151, a tetraspanin transmembrane protein, can directly interact with GLP1R, whose affinity was enhanced by liraglutide intervention in HPC. Knockdown of CD151 in HPC suppressed the expression of p-PXN and integrins, deteriorating cell attachment capacity. Structurally，mutation Arg195 residue of CD151 impeded the GLP1R-CD151 interaction, suggesting the essential role of GLP1R-CD151 cooperation in modulating podocyte adhesion function. Conclusion: Our study first revealed the role of GLP1R in protecting podocyte adhesion function via synergistic interaction with CD51 in FSGS, which shed light on the new therapeutic strategies of GLP1R agonist in non-diabetic renal diseases. Funding: Government Support – Non-U.S.