Key result
In the Goto-Kakizaki rat model of type 2 diabetes, treatment with perindopril significantly reduced blood pressure and cardiac interstitial fibrosis (p<0.05) but had minimal impact on renal structure or function.
Why the study?
Cardio-renal remodeling and response to RAS blockade were analyzed in Goto-Kakizaki rats to ascertain the validity of this model of type 2 diabetes.
Does perindopril improve cardiac and renal structure and function in the Goto-Kakizaki rat model of type 2 diabetes?
Does perindopril improve cardiac and renal structure and function in the Goto-Kakizaki rat model of type 2 diabetes?
p-value: p=<0.05
The Goto-Kakizaki rat demonstrates some features of diabetes-induced cardiorenal syndrome, such as preserved systolic function, impaired relaxation, and cardiac hypertrophy, but its slow disease progression limits its utility as a preclinical model.
BACKGROUND: Patients with diabetes are at a high risk for developing cardiac dysfunction in the absence of coronary artery disease or hypertension, a condition known as diabetic cardiomyopathy. Contributing to heart failure is the presence of diabetic kidney disease. The Goto-Kakizaki (GK) rat is a non-obese, non-hypertensive model of type 2 diabetes that, like humans, shares a susceptibility locus on chromosome 10. Herein, we perform a detailed analysis of cardio-renal remodeling and response to renin angiotensin system blockade in GK rats to ascertain the validity of this model for further insights into disease pathogenesis. METHODS: Study 1: Male GK rats along with age matched Wistar control animals underwent longitudinal assessment of cardiac and renal function for 32 weeks (total age 48 weeks). Animals underwent regular echocardiography every 4 weeks and at sacrifice, early (~24 weeks) and late (~48 weeks) timepoints, along with pressure volume loop analysis. Histological and molecular characteristics were determined using standard techniques. Study 2: the effect of renin angiotensin system (RAS) blockade upon cardiac and renal function was assessed in GK rats. Finally, proteomic studies were conducted in vivo and in vitro to identify novel pathways involved in remodeling responses. RESULTS: GK rats developed hyperglycaemia by 12 weeks of age (p<0.01 c/w Wistar controls). Echocardiographic assessment of cardiac function demonstrated preserved systolic function by 48 weeks of age. Invasive studies demonstrated left ventricular hypertrophy, pulmonary congestion and impaired diastolic function. Renal function was preserved with evidence of hyperfiltration. Cardiac histological analysis demonstrated myocyte hypertrophy (p<0.05) with evidence of significant interstitial fibrosis (p<0.05). RT qPCR demonstrated activation of the fetal gene program, consistent with cellular hypertrophy. RAS blockade resulted in a reduction blood pressure(P<0.05) cardiac interstitial fibrosis (p<0.05) and activation of fetal gene program. No significant change on either systolic or diastolic function was observed, along with minimal impact upon renal structure or function. Proteomic studies demonstrated significant changes in proteins involved in oxidative phosp4horylation, mitochondrial dysfunction, beta-oxidation, and PI3K/Akt signalling (all p<0.05). Further, similar changes were observed in both LV samples from GK rats and H9C2 cells incubated in high glucose media. CONCLUSION: By 48 weeks of age, the diabetic GK rat demonstrates evidence of preserved systolic function and impaired relaxation, along with cardiac hypertrophy, in the presence of hyperfiltration and elevated protein excretion. These findings suggest the GK rat demonstrates some, but not all features of diabetes induced "cardiorenal" syndrome. This has implications for the use of this model to assess preclinical strategies to treat cardiorenal disease.
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Meagher et al. (2021) studied Diabetic cardiomyopathy and nephropathy (n=32). Perindopril erbumine vs. Vehicle was evaluated on Cardiac interstitial fibrosis (p=<0.05). In the Goto-Kakizaki rat model of type 2 diabetes, treatment with perindopril significantly reduced blood pressure and cardiac interstitial fibrosis (p<0.05) but had minimal impact on renal structure or function.
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