#6485 UNI-494 LOWERS URINARY B2-MICROGLOBULIN LEVELS IN RATS

Abstract

Abstract Background and Aims Mitochondrial dysfunction in renal cells play a critical role in the pathophysiology of acute kidney injury (AKI) and chronic kidney disease (CKD). The proximal tubule is the primary sensor and effector in CKD progression and AKI. The measurement of urine Β2-microglobulin (Β2M) is a sensitive assay for proximal tubule injury. Nicorandil, a selective mitochondrial ATP-sensitive potassium channel activator, may be a promising AKI treatment, but its clinical use is limited by serious gastrointestinal side effects and rapid absorption and elimination. UNI-494, a novel nicorandil prodrug designed to improve its pharmacologic properties, may increase the short half-life and improve the safety profile of nicorandil. This study presents the efficacy data on the effects of UNI-494 in a rat ischemia-reperfusion (I/R) model, evaluating biomarkers of renal injury. Method 49 male Sprague-Dawley rats were randomly assigned to 4 groups to evaluate the in vivo efficacy of UNI-494 in a bilateral renal (I/R) model. Group 1, the Sham group, consisted of 10 subjects while groups 2–4 each had 13. Group 1 received no treatment, Group 2 a vehicle, Group 3 10mg/kg of UNI-494, and Group 4 20mg/kg of UNI-494. Treatments were administered as a single dose on Day 0, 1 hour prior to modeling. Body weights were measured on Days -1, 0, and 1. Urine Β2M levels and urinary albumin-to-creatinine ratio (UACR) samples were collected within 24 hours after the surgery using the metabolic cages. Serum blood urea nitrogen (BUN) and creatinine samples were collected on Day -1 (pre-modeling) and 24 hours after modeling. T-tests were used to evaluate statistical differences between groups. Results Β2M levels were significantly lower for the 20 mg/kg UNI-494 dose group compared to the vehicle group, and Β2M content in both UNI-494 dose groups (10 and 20 mg/kg) was significantly lower compared to the vehicle group (Fig. 1). Β2M levels and content were lower for the 20 mg/kg UNI-494 dose group than for the 10 mg/kg dose group (Fig. 1). There was no difference in body weight changes between the UNI-494 dose groups and the vehicle group. There were no statistically significant differences among all groups for serum creatinine and BUN pre-modeling and in UACR. Conclusion Lower levels of urine Β2M levels in the higher UNI-494 dose group compared to the other groups indicate that UNI-494 may have a renoprotective effect. Additionally, the lower levels of Β2M in the higher dose group compared to the lower dose group indicate a dose-response trend. Our study results are consistent with previously published data with nicorandil in a similar rat model of I/R. This potential renoprotective effect should be further investigated.