IDO1 as a new immune biomarker for diabetic nephropathy and its correlation with immune cell infiltration

Yu, Kuipeng; Li, Dengren; Xu, Fuping; Guo, Hao; Feng, Feng; Ding, Yu; Wan, Xiang; Sun, Nan; Zhang, Yang; Fan, Jiahui; Liu, Lei; Yang, Huimin; Yang, Xiaoling

doi:10.1016/j.intimp.2021.107446

Cited by 23 publications

(20 citation statements)

References 30 publications

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“…A small longitudinal study showed that urinary KYNA could differentiate between progressive albuminuria and non-progressive albuminuria in patients with type 1 diabetes [67]. Immunostaining of kidney sections from DKD animal models revealed higher levels of IDO in the diabetic kidney than in control [68], and the levels of IDO were positively correlated with M1 macrophage and monocytes [69].…”

Section: Kp In Ckdmentioning

confidence: 99%

The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease

et al. 2021

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Background: The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington’s disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. Summary: This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.

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Section: Kp In Ckdmentioning

confidence: 99%

The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease

et al. 2021

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“…Therefore, novel and satisfactory strategies are urgently needed to treat DN. There is growing evidence that multiple biological functions are engaged in the pathogenesis of DN, such as immunity, inflammation, and autophagy ( Yang et al, 2019 ; Yang M. et al, 2021 ; Yu et al, 2021 ; Li et al, 2022 ). In our research, starting from autophagy, for the first time, we identified DEARGs in DN vs. normal human renal tubular interstitial cells by bioinformatics analysis, as well as determined a new autophagy-related biomarker for DN, thus providing novel insights into the tubulointerstitial pathogenesis of DN and contributing to the identification of novel therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of P4HB as a novel autophagy-related biomarker in diabetic nephropathy

Bai

Yang

et al. 2022

Front. Genet.

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Diabetic nephropathy (DN), a frequent microvascular complication of diabetes, has been recognized as a primary cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Previous studies found that autophagy of renal tubular epithelial cells plays an important role in DN pathogenesis. Our research aimed to investigate the differentially expressed autophagy-related genes (DEARGs) between DN and healthy renal tubule samples and identify a novel autophagy-related biomarker associated with tubulointerstitial injury in DN. In this study, gene expression profiles of renal tubules from 10 DN patients and 24 healthy controls in the GSE30122 dataset were analyzed, and 43 DEARGs were identified by bioinformatics analysis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and correlation analysis were performed on DEARGs, and the hub gene prolyl 4-hydroxylase subunit beta (P4HB) was screened by protein–protein interaction and verified by utilizing other datasets and stimulating HK-2 cells under high glucose concentration. We found that the expression of P4HB in renal tubules was correlated with renal function. In summary, our research provided novel insights for comprehension of DN molecular mechanisms and identified P4HB as a novel autophagy-related biomarker of DN.

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“…Accumulating evidence indicates a paramount role for immunity and inflammation in the pathogenesis of DKD. To date, several studies have screened genes related to glomerular immune cell infiltration in individuals with DKD [ 20 ]. Relevant tubulointerstitial studies are rare.…”

Section: Discussionmentioning

confidence: 99%

Identification and verification of vascular cell adhesion protein 1 as an immune-related hub gene associated with the tubulointerstitial injury in diabetic kidney disease

Jia

et al. 2021

Bioengineered

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Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), but the pathogenesis is not completely understood. Tubulointerstitial injury plays critical roles in the development and progression of DKD. The present study aimed to investigate the profile of tubulointerstitial immune cell infiltration and reveal the underlying mechanisms between tubular cell injury and interstitial inflammation in DKD using bioinformatics strategies. First, xCell analysis identified immune cells displaying significant changes in the DKD tubulointerstitium, including upregulated CD4 + T cells, Th2 cells, CD8 + T cells, M1 macrophages, activated dendritic cells (DCs) and conventional DCs, as well as downregulated Tregs. Second, pyroptosis was identified as the main form of cell death compared with other forms of programmed cell death. Vascular cell adhesion protein 1 (VCAM1) was identified as the top ranked hub gene. The correlation analysis showed that VCAM1 was significantly positively correlated with pyroptosis and infiltrated immune cells in the tubulointerstitium. Upregulation of VCAM1 in the DKD tubulointerstitium was further verified in European Renal cDNA Bank cohort and was observed to negatively correlate with the glomerular filtration rate (GFR). Our in vitro study validated increased VCAM1 expression in HK-2 cells under diabetic conditions, and pyroptosis inhibition by disulfiram decreased VCAM1 expression, inflammatory cytokine release and fibrosis. In conclusion, our study identified upregulated VCAM1 expression in renal tubular cells, which might interact with infiltrated immune cells, thus promoting fibrosis. The FDA-approved drug disulfiram might improve fibrosis in DKD by targeting tubular pyroptosis and VCAM1 expression.

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IDO1 as a new immune biomarker for diabetic nephropathy and its correlation with immune cell infiltration

Cited by 23 publications

References 30 publications

The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease

The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease

Identification and validation of P4HB as a novel autophagy-related biomarker in diabetic nephropathy

Identification and verification of vascular cell adhesion protein 1 as an immune-related hub gene associated with the tubulointerstitial injury in diabetic kidney disease

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