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High-fat diet triggers chemerin-dependent immune reprogramming that exacerbates acute kidney injury

ABSTRACT: Obesity presents a known risk factor for acute kidney injury (AKI), but the precise mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that short-term high-fat diet (HFD) feeding aggravated kidney injury in AKI mice. Through multi-omics analysis, we identified chemerin (encoded by Rarres2) as a distinctive renal injury-related adipokine enriched in AKI tubular epithelial cells (TECs), particularly following exposure to HFD. Elevated chemerin levels were confirmed in the serum and kidney biopsy samples of AKI patients with obesity, exhibiting a negative correlation with renal function. Rarres2-/- mice were protected from HFD-induced vulnerability toward AKI as well as different types of AKI after standard diet, emphasizing its direct effect on AKI independent of metabolic factors. Mechanism investigation showed the receptor of chemerin-chemerin chemokine-like receptor 1 (CMKLR1) was expressed on renal mononuclear phagocytic cells (MPCs). By single-cell RNA sequencing (scRNA-seq) analysis, unique Cmklr1hi clusters were identified in renal MPCs following AKI, exhibiting enhanced chemotaxis and pro-inflammatory capacity. Functionally, chemerin acted as a chemoattractant to enhance the chemotaxis of Cmklr1hi MPCs. Finally, supplementation of MPCs-derived cytokines reversed kidney injury in Rarres2-/- mice confirming the role of chemerin-CMKLR1 axis in promoting inflammation and kidney damage. Collectively, we identified chemerin as a specific inflammatory and metabolic target that functions through potent pro-inflammatory Cmklr1hi macrophages. Our study suggests that targeting the chemerin-CMKLR1 axis could be a promising therapeutic strategy for AKI patients, especially those with metabolic syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE279061 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

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High-fat diet triggers chemerin-dependent immune reprogramming that exacerbates acute kidney injury

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