Portulaca oleracea L.-Derived extracellular vesicles alleviate renal lipotoxicity in diabetic kidney disease by regulating the NLRP3 pathway.
Abstract
Background
Diabetic kidney disease (DKD) remains a leading indication for renal replacement therapy, with existing drugs having many limitations. Portulaca oleracea L.-derived extracellular vesicles (PO-EVs) exhibit anti-inflammatory, antioxidant, and immune-regulatory properties. However, their function in DKD has yet to be fully elucidated.
Objective
This investigation sought to examine the interplay between lipid metabolism and inflammation in renal tubular epithelial cells in DKD, and to clarify the role and underlying mechanism of PO-EVs in modulating lipid metabolism-inflammation crosstalk to mitigate DKD progression.
Methods
PO-EVs underwent isolation via differential ultracentrifugation and characterization through transmission electron microscopy (TEM), particle size analysis, zeta potential measurement, and multi-omics analysis. In vivo, db/db mice (DKD model) were given PO-EVs intragastrically, with renal function and tissue indicators detected, and mechanisms explored by transcriptomics and proteomics. In vitro, palmitic acid (PA)-induced lipotoxicity in normal rat kidney tubular epithelial cells (NRK-52E) was used to explore the effects of PO-EVs.
Results
PO-EVs significantly enhanced renal function and mitigated renal tissue lipid deposition in db/db mice. They also alleviated PA-induced cellular lipid accumulation and mitochondrial damage, inhibited NLRP3 inflammasome-related proteins, and enhanced fatty acid oxidation (FAO) and ATP synthesis. Suppressing NLRP3 expression markedly improved mitochondrial morphology, reduced lipid accumulation and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression in NRK-52E.
Conclusion
PO-EVs disrupt the metabolism-inflammation vicious cycle by inhibiting NLRP3 and upregulating PGC-1α, thereby mitigating renal lipotoxicity and delaying DKD progression, providing a basis for DKD therapy.