Myocardial infarction accelerates pathological cardiac remodeling and renal impairment post subtotal nephrectomy

Abstract

Purpose: Chronic kidney disease with co-morbid cardiac dysfunction possesses significant worse mortality and mobility in need of further investigation of its pathophysiology and mechanisms. We investigated whether further pathophysiological changes occur when myocardial infarction (MI) follows that of a kidney insult (induced by 5/6 nephrectomy – STNx) on heart and kidney. Methods: STNx/Sham surgery was induced in male Sprague Dawley rats initially and MI/Sham surgery (left anterior descending coronary artery ligation) performed 4 weeks later. Animals were maintained for further 8 weeks. The animals (n=36) were randomized into four groups: Sham-operated STNx + Sham-operated MI (Sham+Sham), Sham-operated STNx + MI (Sham+MI), STNx+Sham-operated MI (STNx+Sham) and STNx+MI. Echocardiography, glomerular filtration rate and blood pressure (BP) were assessed prior to the second surgery and 8 weeks later. Thereafter, tissues were collected for analysis. Results: Survival rate was 100%, 77.8%, 60.9% and 39.8% in Sham+Sham, Sham+MI, STNx+Sham and STNx+MI animals, respectively. Despite no further deterioration in renal function, increased renal interstitial fibrosis (p<0.05) and kidney injury molecule-1 (p<0.001) was observed in the kidney non-infarct zone in STNx+MI vs STNx+Sham animals. Heart weight/body weight ratio was greater in STNx+MI vs STNx+Sham animals (p<0.05), despite no difference in BP was observed. STNx+MI animals had a 28.3% reduction in delta fractional shortening compared to Sham+MI animals (p=0.07). In the non-infarct zone of the left ventricle (LV), STNx+MI animals demonstrated greater cardiomyocyte cross-sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (p<0.01 and p<0.05 respectively) or Sham+MI (p<0.001 and p<0.01 respectively) animals. These changes were associated with significant increases in collagen I gene expression in the LV non-infarct zone in STNx+MI vs STNx+Sham animals (p<0.05). In comparison with STNx+Sham group, phosphorylated p38 MAPK and phosphorylated p44/42 MAPK protein expression were increased in the LV non-infarct zone in STNx+MI animals (p<0.05 and p<0.01 respectively). There were no changes in gene and protein expression in kidney tissues in STNx+MI vs STNx+Sham animals. Conclusions: Myocardial infarction accelerated subtotal nephrectomy–induced renal fibrosis as well as cardiac hypertrophy and fibrosis, and all of these were blood pressure independent. This study established a potential useful model for pathophysiological and mechanistic assessing of cardiorenal syndrome.