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

Abstract

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.

The protective effect of hederagenin on renal fibrosis by targeting muscarinic acetylcholine receptor

“…Qi deficiency and blood stasis are considered by traditional Chinese medicine as common symptoms of renal fibrosis, while Curcumae Rhizoma has the effects of promoting Qi, breaking blood, eliminating accumulation, and relieving pain. Recently, the discovery of some drugs against CKD and the potential targets for the treatment of CKD provide novel sight for developing new treatments [ 2–4 ]. Natural products own widespread biological activities in treatment of some disease [ 5–7 ].…”

5-Hydroxymethylcytosine profiles in plasma cell-free DNA reflect molecular characteristics of diabetic kidney disease

“…VCAM1 (Vascular Cell Adhesion Molecule 1) mainly encodes a cell surface sialoglycoprotein expressed by cytokine-activated endothelium and mediates leukocyte-endothelial cell adhesion and signal transduction that has been extensive-studied in cardiovascular diseases (41, 42). The high expression of VCAM1 in renal tubular cells may promote their interactions with immune cells to affect infiltration, thereby promoting fibrosis (43). At the same time, in vitro studies confirmed that the expression of VCAM1 was increased in HK-2 cells under high glucose conditions, and disulfiram could decrease the expression of VCAM1, the release of inflammatory cytokine, and fibrosis.…”

Stage II of Chronic Kidney Disease—A Tipping Point in Disease Progression?

“…Another puzzle piece in stage 2 is the exclusive detection of vascular cell adhesion protein 1 (VCAM-1), a biomarker of kidney diseases. VCAM-1 enables the adhesion of leukocytes to vascular endothelium, aggravating atherosclerosis and further facilitating inflammation [ 17 , 18 ]. We also observed that proteins related to innate immunity pathways are raised above healthy control group levels in all CKD stages, with a clearly visible peak in CKD2 ( Figure 3 ).…”