PS-BPB06-7: NOVEL MOLECULAR MECHANISMS OF CARDIO-RENAL INTERACTION MEDIATED BY INCREASED SERUM MODIFIED NUCLEOSIDES ASSOCIATED WITH RENAL FAILURE

Abstract

Objective: The number of patients with chronic kidney disease (CKD) continues to rise by population aging. Moreover, CKD patients progress to end-stage renal failure and require renal replacement therapy. Many cohort studies have shown that impaired renal function itself is a risk factor for the development of cardiovascular disease, rather than comorbidities such as diabetes or hypertension. However, the molecular mechanisms are not fully understood. We focused on chemical modifications in RNA and their pathophysiological significance. Previously, we have shown that modified nucleosides, the metabolites of modified RNA, have unique physiological effects. For example, we reported that N6-methyladenosine is a true ligand for the A3 adenosine receptor, and that 1-methylguanosine promotes Zika virus replication in the host. In addition, it was found that a number of modified nucleosides are present in serum and excreted into extracellular spaces like urine. Therefore, we hypothesized that the decreased urinary excretion of modified nucleosides upon renal failure may cause abnormally high levels of modified nucleosides in the blood, which may exert detrimental effects on the heart and vasculature. Methods and Results: First, serum samples were collected from 210 CKD patients, and the correlation between serum modified nucleoside levels and eGFR was investigated. The results showed that several modified nucleosides such as 5-methylcytidine and pseudouridine were inversely correlated with renal function (r2 = -0.76, p < 0.0001; r2 = -0.78, p < 0.0001, respectively). Moreover, we found that 1-methylinosine was inversely correlated with renal function and positively correlated with BNP, a typical marker for heart failure (r2 = -0.82, p < 0.0001 vs. eGFR; r2 = 0.41, p = 0.010 vs. BNP). Next, to explore the possibility of cardiovascular injury associated with this elevation of 1-methylinosine, we examined its effect on vascular endothelial cells. We found that the addition of 1-methylinosine significantly increased cell proliferation using cultured human aortic endothelial cells (p = 0.004, n = 6). Conclusions: Through this study, we found that multiple modified nucleosides are significantly elevated in serum of CKD patients. Furthermore, the elevation of 1-methylinosine in serum can induce abnormal proliferative signals in vascular endothelial cells, which may thereby lead to endothelial damage. In conclusion, these results suggest that the elevated blood levels of modified nucleosides could be a novel marker for vascular injury, and might become a potential target for drug intervention in the cardio-renal interaction.