PLIN5 Protects Against Ang II-Induced Podocyte Lipotoxicity by Interacting With FKBP8 and Preserving Lipid...

Chronic kidney disease (CKD) remains a major global health challenge. Angiotensin II (Ang II)-induced lipotoxicity is an important contributor to podocyte injury. Perilipin 5 (PLIN5) is a lipid droplet-associated protein that helps maintain cellular metabolic homeostasis. However, how PLIN5 protects podocytes from lipotoxic stress remains incompletely understood. In this study, we generated podocyte-specific PLIN5 knockout mice using the Cre-loxP system and induced PLIN5 overexpression in vivo and in vitro. We found that Ang II markedly downregulated PLIN5 expression in podocytes both in vivo and in vitro. Podocyte-specific deletion of PLIN5 aggravated Ang II-induced lipid accumulation, mitochondrial dysfunction and apoptosis, whereas PLIN5 overexpression alleviated these abnormalities. Proteomic screening identified FK506-binding protein 8 (FKBP8), an outer mitochondrial membrane protein, as a PLIN5-interacting partner. Co-immunoprecipitation and proximity ligation assays showed that the PLIN5-FKBP8 interaction was reduced under Ang II stimulation. Functionally, FKBP8 knockdown disrupted lipid droplet-mitochondria contact and exacerbated Ang II-induced podocyte lipotoxicity. Domain-mapping and rescue experiments further demonstrated that the 70-200 amino acid region of FKBP8 is required for PLIN5 binding and for preservation of lipid droplet-mitochondria contact under lipotoxic stress. In addition, disruption of the PLIN5-FKBP8 axis was associated with impaired fatty acid utilisation and altered mitochondrial homeostasis. Collectively, these findings support a model in which PLIN5 protects podocytes, at least in part, by interacting with FKBP8 and preserving lipid droplet-mitochondria contact, thereby limiting Ang II-induced lipotoxic injury.