TRC4186, a Novel AGE-breaker, Improves Diabetic Cardiomyopathy and Nephropathy in Ob-ZSF1 Model of Type 2 Diabetes

Abstract

Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

“…Similarly, obese animals develop interstitial and vascular lesions typical of human DN (Prabhakar et al 2007) including interstitial fibrosis and tubular dilatation and atrophy, interstitial inflammation, and arteriolar thickening. This study and previous reports by us and others (Tofovic et al 2000, Griffin et al 2007, Prabhakar et al 2007, Zhang et al 2007, Rafikova et al 2008, Joshi et al 2009) thus indicate that the ZSF1 rat meets the criteria for progressive experimental diabetic renal disease and suggest that the obese ZSF1 rat may be the best available rat model for close simulation of human DN.…”

“…Similarly, we demonstrated 10-to 25-fold increase in proteinuria with significant mesangial expansion and tubulointerstitial fibrosis in animals older than 40 weeks (Tofovic et al 2000, Zhang et al 2007) and doubling of glomerular basement membrane thickness by 20 weeks of age in obese ZSF1 rats has been reported (Prabhakar et al 2007). Recently, a combined classification for human type-1 and type-2 DN was developed that includes four hierarchical categories of glomerular lesions with separate evaluation for degrees of interstitial and vascular involvement (Tervaert et al 2010); according to these criteria, 20-to 44-week-old obese ZSF1 rats develop class II glomerular lesions characterized by basement membrane thickening and mesangial expansion with mild to moderate (5-30%) glomerulosclerosis (Tofovic et al 2000, Griffin et al 2007, Prabhakar et al 2007, Zhang et al 2007, Rafikova et al 2008, Joshi et al 2009). Importantly, our previous studies indicate that by 50 weeks of age, male obese ZSF1 rats had O50% glomerulosclerosis (Tofovic et al 2000.…”

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy

“…Thus, clinical observations seen with Rosiglitazone and Enaplapril are largely recapitulated in obese ZSF1 rats. In addition, novel and emerging mechanisms have been tested in this model, with promising results [43–46]. In any pre-clinical study, it is important to know when to intervene in a manner appropriate to both the mechanism being tested and the disease stage when therapeutic dosing would likely begin in a clinical setting.…”

The Evolving Face of Heart Failure Associated with Elevated Cardio-Metabolic Risk Factors

“…Although the exact mechanism of AGE breaking is not very clear, reduction in AGE load and all ensuing downstream events, including attenuation of the associated inflammatory response, likely contributed to the improvement observed on treatment with TRC4186. These outcomes are substantially supported by suitable histopathological and immunohistochemical findings (Joshi et al, 2009). AGE breakers are likely to be beneficial in diabetic heart failure patients in whom there is usually a significant component of diastolic dysfunction and vascular unresponsiveness, when assessed for meaningful clinical endpoints such as physical attributes of Minnesota Living with Heart Failure Questionnaire and OUES, that are able to assess not only myocardial reserve but also vascular (nutritive perfusion) reserve.…”