Cardiovascular dysfunction is caused by pre‐existing hydronephrosis in young lean, obese and diabetic Zucker rats

Abstract

Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats are models of insulin resistance and Type 2 diabetes often used to examine the impact of metabolic disease on cardiovascular physiology. However, there have been reports of renal abnormalities in lean and obese ZDF animals, which question their suitability for such studies. Therefore, we evaluated the LV pressure-volume relationship in vivo in 14wk old, male homozygous Zucker lean (ZL), ZO, ZDF and Sprague Dawley (SD) rats. Heart and kidneys were removed, blood glucose, HbA1c and urine albumin and creatinine levels determined. HbA1c and glucose were higher (p<0.05) and creatinine excretion lower (p<0.05) in ZO and ZDF obese animals compared to SD. Although LV contractility was normal in all groups, chamber stiffness was increased in ZO and the time constant for relaxation was increased in ZDF compared to SD (p<0.05); arterial elastance was increased (p<0.05) in both ZL and ZO groups. Ejection fraction was lower (p<0.05) only in the ZDF group. Morphologic examination revealed hydronephrosis ranging from mild to moderate in 50% ZL and mild to severe in 50% ZO and 100% ZDF rats; all SD kidneys appeared normal. There was evidence of diastolic dysfunction in ZO and ZDF rats and increased arterial stiffness in ZL rats in the presence of renal pathology. These abnormalities in relatively young animals may be secondary to a primary renal abnormality that affects cardiovascular function via a neurohormonal mechanism independent of diabetes. These findings question the validity of the ZDF model to study the effects of diabetes on cardiovascular function. Supported by NIH HL077100, HL67464.