The Goto Kakizaki rat: Impact of age upon changes in cardiac and renal structure, function

Abstract

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.

A Holistic View of the Goto-Kakizaki Rat Immune System: Decreased Circulating Immune Markers in Non- Obese Type 2 Diabetes

“…The extracted biological pathways from the gene expression profiles confirmed a downregulated pattern of most involved genes in the GK rats. The most prominent gene pathway was diabetic cardiomyopathy, fitting previous reports of ventricular hypertrophy, impaired diastolic function, and cardiomyopathy in GK rats ( 66 , 67 ) that may be mediated by CRP ( 68 ). This peripheral gene expression profile contrasts sharply with the inflammatory profile of the GK rat pancreatic islets, where similar to diabetic human islets ( 69 ), we consistently show increased pro-inflammatory cytokine levels, associated with increased pro-inflammatory immune cell numbers around and within the pancreatic islets ( 13 , 14 , 35 ).…”

Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models

“…More extensive phenotyping of these rats has shown that by 48 weeks of age these animals exhibit concentric LV hypertrophy associated with adverse myocardial remodeling, pulmonary congestion, and diastolic dysfunction. 106 Whereas their LVEF at 48 weeks is within the normal range for rats in general, it is important to note that LVEF significantly declines from 24 to 48 weeks in these animals, which is not entirely consistent with clinical HFpEF.…”

Guidelines on models of diabetic heart disease

“…Female GK rats have reduced myocardial blood flow and contractility at the age of 8 to 13 mo, as assessed by perfusion and cine MRI ( 167 ). Ultrasound echocardiography studies have demonstrated that male GK rats have preserved systolic but reduced diastolic function at 6 to 7 mo of age, indicative of a diabetic cardiomyopathy phenotype ( 168 , 169 ), whereas systolic function declines at 12 mo of age ( 170 ). Other studies show preserved basal contractility in isolated perfused hearts ( 171 ) and in isolated ventricular myocytes ( 172 ).…”