Septic acute kidney injury (AKI) is commonly associated with renal dysfunction and high mortality in patients. Owing to the rapid and violent occurrence of septic AKI with inflammation, there are no effective therapies to clinically treat it. Embelin, a natural product, has a potential regulatory role in immunocytes. However, the role and mechanism of embelin in septic AKI remains unknown. This study aimed to elucidate the role of embelin in macrophage regulation in lipopolysaccharide (LPS)-induced septic AKI. Embelin was intraperitoneally administered to mice after LPS injection. And bone marrow-derived macrophages (BMDMs) were subsequently isolated from the mice to explore the immunomodulatory role of embelin in macrophages. We found that embelin attenuated renal dysfunction and pathological renal damage in the LPS-induced sepsis mouse model. Molecular docking predicted that embelin could bind to phosphorylated NF-κB p65 at the ser536 site. Embelin inhibited the translocation of NF-κB p65 via phosphorylation at ser536 in LPS-induced AKI. It also reduced the secretion of IL-1β and IL-6 and increased the secretion of IL-10 and Arg-1 of BMDMs and mice after LPS stimulation, indicating that embelin suppressed macrophage M1 activation in LPS-induced AKI. Therefore, embelin attenuated LPS-induced septic AKI by suppressing NF-κB p65 at ser536 in activated macrophages. This study preclinically suggests a therapeutic role of embelin in septic AKI.

Drug-induced nephrotoxicity remains a common problem after exposure to medications and diagnostic agents, which may be heightened in the kidney microenvironment and deteriorate kidney function. In this study, the toxic effects of fourteen marked drugs with the individual chemical structure were evaluated in kidney cells. The quantitative structure-activity relationship (QSAR) approach was employed to investigate the potential structural descriptors of each drug-related to their toxic effects. The most reasonable equation of the QSAR model displayed that the estimated regression coefficients such as the number of ring assemblies, three-membered rings, and six-membered rings were strongly related to toxic effects on renal cells. Meanwhile, the chemical properties of the tested compounds including carbon atoms, bridge bonds, H-bond donors, negative atoms, and rotatable bonds were favored properties and promote the toxic effects on renal cells. Particularly, more numbers of rotatable bonds were positively correlated with strong toxic effects that displayed on the most toxic compound. The useful information discovered from our regression QSAR models may help to identify potential hazardous moiety to avoid nephrotoxicity in renal preventive medicine.

BACKGROUND: Cardiac surgery-associated acute kidney injury (AKI) can increase the mortality and morbidity, and the incidence of chronic kidney disease, in critically ill survivors. The purpose of this research was to investigate possible links between urinary metabolic changes and cardiac surgery-associated AKI.
METHODS: Using ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry, non-targeted metabolomics was performed on urinary samples collected from groups of patients with cardiac surgery-associated AKI at different time points, including Before_AKI (uninjured kidney), AKI_Day1 (injured kidney) and AKI_Day14 (recovered kidney) groups. The data among the three groups were analyzed by combining multivariate and univariate statistical methods, and urine metabolites related to AKI in patients after cardiac surgery were screened. Altered metabolic pathways associated with cardiac surgery-induced AKI were identified by examining the Kyoto Encyclopedia of Genes and Genomes database.
RESULTS: The secreted urinary metabolome of the injured kidney can be well separated from the urine metabolomes of uninjured or recovered patients using multivariate and univariate statistical analyses. However, urine samples from the AKI_Day14 and Before_AKI groups cannot be distinguished using either of the two statistical analyses. Nearly 4000 urinary metabolites were identified through bioinformatics methods at Annotation Levels 1-4. Several of these differential metabolites may also perform essential biological functions. Differential analysis of the urinary metabolome among groups was also performed to provide potential prognostic indicators and changes in signalling pathways. Compared with the uninjured kidney group, the patients with cardiac surgery-associated AKI displayed dramatic changes in renal metabolism, including sulphur metabolism and amino acid metabolism.
CONCLUSIONS: Urinary metabolite disorder was observed in patients with cardiac surgery-associated AKI due to ischaemia and medical treatment, and the recovered patients\' kidneys were able to return to normal. This work provides data on urine metabolite markers and essential resources for further research on AKI.

Macrophages are typically identified as classically activated (M1) macrophages and alternatively activated (M2) macrophages, which respectively exhibit pro- and anti-inflammatory phenotypes, and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation, injury, and repair processes. Recent studies indicate that tissue cells and macrophages interact via the release of small extracellular vesicles (EVs) in processes where EVs released by stressed tissue cells can promote the activation and polarization of adjacent macrophages which can in turn release EVs and factors that can promote cell stress and tissue inflammation and injury, and vice versa. This review discusses the roles of such EVs in regulating such interactions to influence tissue inflammation and injury in a number of acute and chronic inflammatory disease conditions, and the potential applications, advantage and concerns for using EV-based therapeutic approaches to treat such conditions, including their potential role of drug carriers for the treatment of infectious diseases.

Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), are associated with inflammation. The mechanism that regulates inflammation in these renal injuries remains unclear. Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase, was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice. Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries. Furthermore, increased H3K18ac was recruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice. In vitro studies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led to downregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-κB (p50), and MCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level. Consistent with these, overexpression of PCAF enhanced the expression of inflammatory molecules. Furthermore, PCAF deficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, as well as inhibited palmitate-induced upregulation of these inflammatory molecules. In summary, the present work demonstrates that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases.