Differential impact of C57BL/6 substrains on the development of type 1 cardiorenal syndrome

Abstract

Introduction

C57BL/6 is one of the most important mouse strains for preclinical research. However, the two main substrains, C57BL/6 J and C57BL/6 N have developed over time genetic mutations that could lead to differences in response to pathology. The heart and kidneys are closely linked, and dysfunction of either organ can affect the other, leading to a pathological condition known as cardiorenal syndrome (CRS). Type 1 CRS is characterized by a primary acute cardiac injury, leading to a secondary renal disease. Although some studies have shown differences on the development of acute cardiovascular or renal diseases between these two substrains, the influence of the C57BL/6 background on the development of type 1 CRS remains poorly understood.

Objective

The goal of this project is to determine and compare the cardiac and renal outcomes and the development of type 1 CRS after a primary cardiac insult between the two main C57BL/6 substrains.

Method

Fourteen weeks old C57BL/6NRj (B6 N) and C57BL/6JRj (B6 J) male mice were subjected to permanent coronary artery ligation to generate acute myocardial infarction (MI) or sham surgery. Cardiac and renal functions were analysed by echography and transdermal glomerular filtration rate, 7 and 21 days after the surgery. Cardiac or renal remodeling analysis were performed after 21 days.

Results

In both substrains, left ventricular ejection fraction was reduced 21 days after acute MI as compared with their respective sham (P < 0.0001). After MI, both substrains significantly developed cardiac hypertrophy, as evidenced by the similar increase of heart weight (+25% in both groups, compared with their respective sham) and cardiomyocyte size (+31% in B6 J and +18% in B6 N, compared with their respective sham). Regarding the renal outcome, acute MI resulted in an increase in renal artery pulsatility index (+22% compared with sham), and a decrease in glomerular filtration rate (-20% compared with sham) only in B6 J mice, whereas both renal parameters remained unchanged in B6 N background.

Conclusion

Overall, our results show that an acute cardiac injury led to the same level of primary cardiac dysfunction in both B6 J and B6 N substrains, whereas only the B6 J develop a secondary kidney disease and a type 1 CRS.