Characterization of Early Functional, Structural and Molecular Alterations in a Rat Model of Cardiorenal Syndrome Type Iv: Role of BMP-2

Objective: Cardiorenal Syndrome type IV (CRS-IV) is a common complication of chronic kidney disease (CKD) and a high-risk syndrome with poor prognosis. However, pathogenic mechanisms remain elusive. Our objective was to characterize early cardiac structural, functional, and molecular alterations in Munich Wistar Frömter (MWF), a rat model with established CKD. Design and method: Cardiac function, rhythm and structure were analyzed in aging 22- and 45-week-old Wistar and MWF rats (n=8/group) by electrocardiogram (ECG) and cardiac magnetic resonance imaging (CMRI). Hearts were dissected after the sacrifice and ventricle mRNA was extracted for q-RT-PCR. Results: From 22 weeks of age, MWF showed a defective ventricular repolarization (longer QT, QTc, JT and Tpeak-Tend) compared to Wistar rats. These ventricular electrical alterations relate to the presence of left ventricular (LV) hypertrophy supported by increased heart weight, LV wall thickness and higher expression of atrial and brain natriuretic peptides (Anp and Bnp). MWF rats also exhibited significantly lower systolic, diastolic and stroke volumes and a reduced cardiac output with no changes in the ejection fraction compared to Wistar rats. At 45 weeks of age, the PR interval and P duration were increased in MWF rats compared to Wistar, indicating the development of atrial conduction dysfunction. LV expression of bone morphogenetic protein 2 (Bmp-2), which has been proposed as an antifibrotic cytokine, was 4-fold higher in MWF, whereas Tgf-beta was significantly lower and negatively correlated with Bmp-2 in MWF. Conclusions: During aging CKD evolves into CRS-IV through the development of LV hypertrophy and dysfunction followed at later ages by atrial damage. Since Bmp-2 downregulates profibrotic Tgf-beta expression it appears that the observed upregulation of Bmp-2 may represent an adaptive, however non-compensatory, cardiac response in the development of CRS-IV in this model.