#2529 Nanoparticle-mediated Klotho gene therapy prevents kidney disease progression via PPARα pathway

Abstract Background and Aims Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Method Polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs) were constructed that can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. Two acute kidney injury-chronic kidney disease transition animal models were used to investigate the effect of PPSK NPs in vivo. Results In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanistically, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. Conclusion In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.