PLIN5 Protects Against Ang II ‐Induced Podocyte Lipotoxicity by Interacting With FKBP8 and Preserving Lipid Droplet–M

ABSTRACT

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.