Laptm4a mediates renal ischemia-reperfusion injury by regulating the UNC5B-AKT/mTOR signaling pathway.

Introduction: Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), but specific therapeutic targets are lacking.Lysosomal Protein Transmembrane 4A (LAPTM4A), a four transmembrane-spanning protein mainly localized in endosomes and lysosomes,however, its pathological role in AKI remains unexplored. Methods: To investigate the impact of LAPTM4A on renal IRI, we developed an in vivo renal IRI model utilizing LAPTM4A knockout mice, alongside an in vitro hypoxia-reperfusion(H/R) model employing shRNA to knockdown LAPTM4A in HK2 cell. A comprehensive suite of methodologies, including Western blotting, qPCR, CCK-8 assay, LDH assay, TUNEL assay, ELISA, and histopathological analysis, was employed to evaluate cell proliferation, apoptosis, and inflammatory cytokine levels. Results: We found that the expression of Laptm4a was upregulated in kidney of renal IRI mice and HK2 cell induced by hypoxia-reoxygenation(H/R). Knockout of Laptm4a improved renal function , attenuated tubular injury and reduced inflammatory cell infiltration and apoptosis, whereas overexpression exacerbated the injury.Mechanistically Laptm4a exacerbated renal IRI through suppression of the UNC5B-AKT-mTOR protective signaling pathway. Conclusions: Our findings suggest that Laptm4a exacerbates inflammation and apoptosis by inhibiting the UNC5B-PI3K-AKT signaling pathway. This study provides a novel elucidation of the role of Laptm4a as a critical positive regulator of IRI, offering preliminary preclinical insights that may inform future investigations into therapeutic strategies.