Abstract P373: Nuclear Receptor 4As (NR4A) Expression In Patients With Chronic Kidney Disease

Abstract

Background: Nuclear Receptor 4As (NR4A1, NR4A2, and NR4A3) play important metabolic, immune, and cardiovascular functions. These receptors also play a role in mitochondrial function. Patients with chronic kidney disease (CKD) have impaired mitochondrial function and biogenesis. Thus, in this study, we hypothesize that NR4As are downregulated in muscles in patients with CKD. Methods: In a cross-sectional study, we performed RNA sequencing in skeletal muscle biopsies from three groups; controls (n=13), patients with CKD 3-5 not yet on hemodialysis (n=13), and patients on maintenance hemodialysis (MHD, n=10). Total RNA was extracted to construct libraries for total RNA sequencing using Illumina NovaSeq 6000 system. Differentially expressed genes were identified with a false discovery rate (FDR) <0.05 and fold change > 2. We focused our analysis on genes involved in mitochondrial biogenesis. Results: Groups were matched by gender, body mass index, and history of diabetes and hypertension. There was no difference in markers of mitochondrial biogenesis between controls and patients with CKD 3-5. We only found a significant decrease in NR4A1 and NR4A3 gene expression in patients on MHD ( Figure 1 ) compared to control (p=0.006 and p= 0.02; NR4A1 and NR4A3, respectively) and to patients with CKD 3-5 (p=8.85E-05 and p=0.005; NR4A1 and NR4A3, respectively). Conclusions: NR4A1 and NR4A3 were downregulated in muscle biopsies from patients on MHD. These findings may explain the reduced mitochondrial content and impaired mitochondrial function in patients with CKD. Further studies should evaluate the benefit of NR4As-targeted therapies to prevent mitochondrial dysfunction in CKD.