AFM negatively regulates the infiltration of monocytes to mediate sepsis-associated acute kidney injury

Abstract

BackgroundSepsis is organ dysfunction due to the host’s deleterious response to infection, and the kidneys are one of the organs damaged in common sepsis. Sepsis-associated acute kidney injury (SA-AKI) increases the mortality in patients with sepsis. Although a substantial volume of research has improved the prevention and treatment of the disease, SA-SKI is still a significant clinical concern.PurposeAimed to use weighted gene co-expression network analysis (WGCNA) and immunoinfiltration analysis to study SA-AKI-related diagnostic markers and potential therapeutic targets.MethodsImmunoinfiltration analysis was performed on SA-AKI expression datasets from the Gene Expression Synthesis (GEO) database. A weighted gene co-expression network analysis (WGCNA) analysis was performed on immune invasion scores as trait data, and modules associated with immune cells of interest were identified as hub modules. Screening hub geneset in the hub module using protein-protein interaction (PPI) network analysis. The hub gene was identified as a target by intersecting with significantly different genes screened by differential expression analysis and validated using two external datasets. Finally, the correlation between the target gene, SA-AKI, and immune cells was verified experimentally.ResultsGreen modules associated with monocytes were identified using WGCNA and immune infiltration analysis. Differential expression analysis and PPI network analysis identified two hub genes (AFM and GSTA1). Further validation using additional AKI datasets GSE30718 and GSE44925 showed that AFM was significantly downregulated in AKI samples and correlated with the development of AKI. The correlation analysis of hub genes and immune cells showed that AFM was significantly associated with monocyte infiltration and hence, selected as a critical gene. In addition, Gene single-enrichment analysis (GSEA) and PPI analyses results showed that AFM was significantly related to the occurrence and development of SA-AKI.ConclusionsAFM is inversely correlated with the recruitment of monocytes and the release of various inflammatory factors in the kidneys of AKI. AFM can be a potential biomarker and therapeutic target for monocyte infiltration in sepsis-related AKI.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…It includes 39 AKI and 9 normal control samples, we found 956 DEGs (including 478 up regulated genes and 478 down regulated genes). Studies suggested that PLG (plasminogen) [53], AFM (afamin) [54] and UMOD (uromodulin) [55] are involved in advancement of AKI. PLG (plasminogen) [56], GSTA1 [57], AGTR1 [58], CYP4A11 [59], UMOD (uromodulin) [60] and IL1RL1 [61] might be a potential prognostic markers or therapeutic targets against the cardiovascular disorders.…”

“…Studies had shown that PLG (plasminogen) [69], GSTA1 [70], AGTR1 [71] and CYP4A11 [72] were associated with liver disease. PLG (plasminogen) [73], AFM (afamin) [54], AGTR1 [74] and UMOD (uromodulin) [75] might be a potential therapeutic target for sepsis. Abnormal regulation of PLG (plasminogen) [76], AFM (afamin) [77], GSTA1 [78], AGTR1 [79] and UMOD (uromodulin) [80] are associated with diabetes mellitus.…”

Prognostic Value of the Baseline and Early Changes in Monocyte-to-Lymphocyte Ratio for Short-Term Mortality among Critically Ill Patients with Acute Kidney Injury

“…Monocytes migrate into the injured kidney and differentiate into macrophages, further infiltrating tissue and aggravating ischemic murine ischemic renal injury by secreting pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor-α, and IL-1β [28][29][30]. Another experimental study by Guo et al found that decreased expression of the gene AFM could lead to increased monocyte infiltration, thereby promoting renal inflammation and injury in murine models of sepsis-associated AKI [31]. Furthermore, it has been demonstrated that regulatory T lymphocytes (Treg) could exert protective effects in AKI, reducing inflammation and promoting tissue repair through the anti-inflammatory cytokine IL-10-mediated suppression of the innate system [32].…”

Sepsis-Associated Acute Kidney Injury: Where Are We Now?

“…Apart from serum and urinary biomarkers, there is ongoing research regarding molecular biomarkers of SA-AKI. In particular, gene expression profiles in SA-AKI together with biomarkers stemming from proteomics and metabolomics have revolutionized the field of SA-AKI in terms of diagnosis and prognosis [ 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Regarding gene expression profiles, Guo et al have very recently demonstrated that the AFM gene, also called “afamin”, which is a member of the albumin family of genes, may be a surrogate biomarker for SA-AKI.…”

“…Regarding gene expression profiles, Guo et al have very recently demonstrated that the AFM gene, also called “afamin”, which is a member of the albumin family of genes, may be a surrogate biomarker for SA-AKI. More specifically, using the Gene Expression Omnibus (GEO) Synthesis database and Weighted Gene Co-expression Network Analysis (WGCNA), they documented afamin as a biomarker of SA-AKI being inversely associated with the recruitment of monocytes and the levels of various inflammatory factors [ 57 ]. By using the GEO database as well, Liu et al found that 7 out of the 15 hub genes are involved in the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.…”