Combination therapy of olmesartan/exenatide decreases renal ER stress in a rat model of metabolic syndrome (1088.5)

Abstract

The OLETF rat is a model of metabolic syndrome, a condition associated with increased activation of RAS and endothelin (ET) systems, renal dysfunction, hypertension and impaired insulin signaling; however, the specific molecular mechanisms that lead to renal dysfunction during metabolic syndrome remain unclear. We hypothesized that this condition is associated with elevated renal ER stress, and that treatment with olmesartan (AT1 receptor blocker; ARB), exenatide (glucagon‐like peptide‐1 analog; EXE), or combination therapy (ARB+EXE), would decrease renal expression of ET, NOS and ER stress markers. OLETF rats and their controls (LETO) were subjected to individual/combined treatments of ARB (10ug/kg/day; n=4) and EXE (5ug/kg/day; n=7) for 6 weeks. Whole kidney tissue was analyzed by qRT‐PCR. Individual drug treatment of OLETF rats led to increased relative mRNA expression of ET system (ARB vs. EXE, fold increase; ET: 2.61 ± 0.5 vs. 3.66 ± 1.0; ETA: 1.58 ± 0.5 vs. 3.62 ± 1.1 and ETB: 1.29 ± 0.5 vs. 3.59 ± 0.9), ER stress (GRP78: 1.26 ± 0.6 vs. 2.05 ± 0.5; CHOP: 2.56 ± 0.8 vs. 4.05 ± 1.1 and spliced XBP‐1: 0.70 ± 0.3 vs. 2.12 ± 0.7), and NOS system (NOS1: 2.47 ± 1.1 vs. 3.89 ± 1.2; NOS3: 1.28 ± 0.6 vs. 2.98 ± 1.0). All markers were ameliorated after combined ARB+EXE treatment. In conclusion, these results suggest that a combination ARB+EXE therapy is a plausible preventive treatment for renal dysfunction associated with metabolic syndrome.