Abstract 17007: Unveiling the Immunological and Endocrine Transformations of Veins in Chronic Kidney Disease Through MYCN-AP1 Signaling Amplification

Abstract

Introduction: The predominant selection of hemodialysis as the optimal treatment approach for patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD). Thus, upper extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the transcriptome of veins and primes them for arteriovenous fistula (AVF) failure. Hypothesis: we hypothesized that CKD reprograms and transdifferentiates veins into a specialized immune endocrine organ thereby accelerating vascular inflammation. Methods: we performed transcriptomic analyses of bulk RNA sequencing data of veins isolated from 48 CKD patients and 20 non-CKD controls. Results: Our data showed that: 1) CKD induces vein conversion into immune organs through upregulation of 13 cytokine and chemokine genes, along with over 50 canonical and non-canonical secretome gene; 2) Enhancement of innate immune responses in CKD through upregulation of 12 innate immune response genes and 18 cell membrane protein genes, promoting intercellular communication including CX3CR1 chemokine signaling; 3) CKD induces upregulation of 5 endoplasmic reticulum protein-coding genes and 3 mitochondrial genes, resulting in impaired mitochondrial bioenergetics and immunometabolic reprogramming; 4) Altered fibrogenic processes in veins during CKD through upregulation of 20 fibroblast genes and 6 fibrogenic factors, leading to increased susceptibility to AVF failure; 5) Reprogramming of cell death and survival programs in CKD; 6) Reprogramming of protein kinase signal transduction pathways and upregulation of SRPK3 and CHKB in CKD; and 7) Transcriptomic reprogramming of veins and upregulation of MYCN, AP1, and Additional 11 transcription factors in CKD: implications for embryonic organ development, positive regulation of developmental growth, and vein muscle structure development. Conclusion: The findings unveil veins as immune-endocrine organs and illuminate the impact of CKD in upregulation of secretomes, immune cell differentiation, and vascular cell dynamics.