Abstract 17305: Activation of Soluble Guanylate Cyclase Ameliorates the Progression of Glucose Intolerance and Nephropathy in Obese ZSF1 Rats

• Published in: Circulation (New York, N.Y.) N.Y.), 2016-11, Vol.134 (Suppl_1 Suppl 1), p.A17305-A17305
• Main Authors: da Cunha, Valdeci, Shah, Kashmira, Price, Olga, Sinz, Christopher J, Kim, Ronald M
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

IntroductionRecent data suggests that activation of the NO-soluble guanylate cyclase (sGC)-cyclic cGMP system has potential metabolic effects, in addition to the regulation of vascular tone. The development of specific, potent activators of sGC provides an opportunity to explore the role of sGC in the regulation of glucose metabolism and related cardiovascular end-organ damage.MethodEleven-week old male ZSF-1 rats were used in this study. A novel heme-independent activator of sGC (MRL-001) was administered at a dose of 1 mg/kg/day by oral gavage for 8 weeks, and the effects on glucose tolerance and development of diabetic nephropathy were examined.ResultsAdministration of MRL-001 prevented the progression of glucose intolerance, determined by oral glucose tolerance test (OGTT). At the end of 8 weeks of treatment, plasma levels of nonfasting glucose, triglycerides (TG) and free fatty acids were significantly lower in animals treated with MRL-001 compared with vehicle-treated animals. Histopathologic assessment revealed a significant attenuation in the severity of histological markers of diabetic nephropathy (tubular dilation and degeneration, protein casts) in the kidneys of rats treated with MRL-001. Moreover, urinary excretion of glucose, albumin, markers of tubular damage (N-acetyl glucosaminidase and alpha glutathione S-transferase) and oxidative stress (8-isoprostanoid and 11-dehydro-thromboxane B2) were also reduced by the treatment.ConclusionCollectively, the present study demonstrates that chronic administration of a novel heme-independent activator of sGC evoked a distinct and significant improvement in glucose regulation and progression of diabetic nephropathy in ZSF1 rats. These data suggest novel mechanisms of metabolic regulation and nephropathy associated with diabetes.