Abstract 15912: MicroRNA-92a Mediates Endothelial Dysfunction in Chronic Kidney Disease
Introduction: The emerging field in cardiorenal syndrome (CRS) emphasizes the crucial link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Despite the epidemiological evidence supporting the causal relationship between CKD and CVD, the molecular and cellular mechanisms underlying CRS remain unclear. The accumulation of uremic toxins in CKD induces oxidative stress and endothelial dysfunction, further exacerbating kidney damage. Herein, we investigated the role of microRNA-92a (miR-92a), an oxidative-stress responsive miR, in CKD-induced endothelial dysfunction, and its translational relevance.
Hypothesis: CKD induces miR-92a in the endothelium, and thereby activate endothelial innate immune response and promote endothelial dysfunction.
Methods and Results: In a derivation cohort of CKD patients, circulating levels of miR-92a was significantly increased. This finding was verified in two validation cohorts. Data from 184 patients recruited from 3 sites revealed that circulating miR-92a level is inversely correlated with estimated glomerular infiltration rate. Treating cultured endothelial cells (ECs) with CKD sera or protein-bound uremic toxins (e.g. indole sulfate) induces miR-92a, which suppresses its targets, i.e. endothelial protective molecules SIRT1, Krüppel-like factor 2 (KLF2), and KLF4. In the adenine-induced CKD rat model, miR-92a is increased in the vascular endothelium, endothelial-derived microparticles, as well as the whole serum.
Conclusions: Uremic toxins accumulated in CKD increase oxidative stress-responsive miR-92a in the vascular endothelial cells (ECs), which promotes endothelial dysfunction and vascular damage. Circulating levels of miR-92a may be useful for the prognosis/diagnosis of vascular dysfunction in CKD. Targeting miR-92a may be a promising strategy to ameliorate endothelial dysfunction in CKD.
Author Disclosures: F. Shang: None. S. Wang: None. C. Hsu: None. Y.E. Shiu: None. P. Huang: None. J.Y. Shyy: None. Z. Chen: None.
- © 2016 by American Heart Association, Inc.