ABSTRACT Acute kidney injury (AKI) is a clinical syndrome associated with severe morbidity and high mortality, for which there are no currently effective therapies. Aging, a state associated with Klotho protein decline, is an independent risk factor for AKI development and progression. Here, we report that Klotho‐derived peptide 1 (KP1), a small peptide that recapitulates the renoprotective potential of Klotho, effectively protects against AKI in mouse models induced by either cisplatin or ischemia‐reperfusion injury. KP1 treatment improved kidney function, ameliorated structural damage, inhibited tubular cell apoptosis, and preserved mitochondrial integrity in both models. Mechanistically, KP1 entered kidney proximal tubular epithelial cells via endocytosis, directly targeted the mitochondrial protein ATPase family AAA domain‐containing protein 3A (ATAD3A), and prevented its degradation, and preserved its function. By interacting with the hypoxia inducible gene 1 (HIG1) domain family member 2A (HIGD2A) and maintaining its expression and function within the mitochondria, ATAD3A prevented cytochrome c release and inhibited caspase activation following injury, thereby alleviating renal tubular cell apoptosis. Collectively, these studies demonstrate that KP1 is a promising therapeutic agent for AKI by directly targeting and preserving mitochondrial integrity. Our findings also lay the groundwork for developing novel therapeutic strategies to treat diseases associated with mitochondrial dysfunction.
Xiaoyao Zhang, Shih-Hua Lin, Tianyu Wu et al.· Advancement of science· 0 citations
INTRODUCTION
Acute kidney injury (AKI) is a severe clinical syndrome associated with high morbidity and mortality, and it possesses high risk of progression to chronic kidney disease (CKD). Renal infiltration of inflammatory cells, particularly macrophages, plays a key role in driving the progression from AKI to CKD.
METHODS
We performed single-cell RNA sequencing and spatial transcriptomics analyses on mouse kidney tissues after unilateral ischemia-reperfusion injury (UIRI) at multiple time points (sham, 12 h, 1 day, 4 days, and 10 days post-UIRI). Immunofluorescence, flow cytometry, Western blotting, co-immunoprecipitation, surface plasmon resonance and immunohistochemical staining were applied to investigate protein expression and function.
RESULTS
Six distinct mononuclear phagocyte (MNP) subpopulations were identified and each of them exhibited a unique set of gene expression pattern. In particular, we uncovered an injury-induced, spatially distinct macrophage subset with specific profibrotic properties, named as pro-fibrotic macrophages (PFMs). During the progression of AKI to CKD, PFMs secreted thrombospondin-1 (THBS1), which interacted with and activated LDL receptor-related protein 1 (LRP1) on adjacent interstitial fibroblasts, thereby promoting fibroblast activation and proliferation. In cultured kidney fibroblasts, THBS1 induced fibroblast activation and matrix production, and blockade or knockdown of LRP1 abolished this effect. Furthermore, THBS1 activated a cascade of LRP1 downstream signaling mediators including focal adhesion kinase, protein kinase B, and extracellular signal-regulated kinase 1 and 2. THBS1 also promoted TGF-β1 activation in a LRP1-dependent manner in fibroblasts. In humans, urinary THBS1 levels predicted the rate of CKD progression.
CONCLUSION
These studies identify a unique subset of pro-fibrotic macrophages that drive fibroblast activation through THBS1/LRP1 signaling in a spatially confined setting. Our findings suggest that PFMs-derived THBS1 contributes to the progression from AKI to CKD.
Liuyan Xiao, Yinyi Long, Xue Hong et al.· Journal of Advanced Research· 0 citations
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