#2359 Kinetic modifications in cardiac remodeling in a rat model of CKD
Authors: Boukhaled Juliana , Cortijo Irene , Laget Jonas , Duranton Flore , Jover Bernard , Gayrard Nathalie , Ciscart Angel Argiles , Raynaud Fabrice 
Published: May 2024

Abstract

Background and Aims
The bi-directional relationship between the kidneys and heart leads to different forms of cardiorenal syndrome (CRS) in which acute or chronic dysfunction in one organ affects the other. CRS type 4 is characterized by chronic kidney disease leading to the impairment of cardiac function through diastolic dysfunction and cardiac remodeling, such as fibrosis and hypertrophy. The progression of CRS type 4 occurs dynamically thus identifying key changes could prove beneficial for treatment and prediction of outcome for the patients. This present study assessed the impact on heart remodeling and function after 12 and 24 weeks of chronic kidney disease in rats undergoing subtotal nephrectomy.

Method
Twelve-week-old Sprague Dawley male rats either underwent 5/6 nephrectomy (SNX) or Sham operated and were sacrificed at 12 or 24 weeks after kidney infarction. Serum creatine levels were assessed using the epoc® Blood Analysis System. Before sacrifice, a catheter was inserted into the right carotid artery for systolic arterial pressure (SAP) measurement. Echocardiography (VisualSonics/Fujifilm) was performed under isoflurane anesthesia. To determine the diastolic function of the heart, mitral flow was assessed and recorded using a pulse-wave doppler. The peak early filling (E wave)-to-late diastolic filling (A wave) ratio (E/A) as well as E deceleration time was used to determine diastolic function. Left Ventricle posterior wall thickness (LVPW_S) was measured during end-systole and end-diastole. Image analyses were performed using VisualSonics Vevolab 3.1.0 software. Fibrosis of the kidney and left ventricle was determined through Sirius Red histology staining. The mRNA expression levels of FGF23 and GDF-15 were measured through qPCR. Unpaired T-test, Non-parametric, or One-way ANOVA were applied, and log transformation was performed when applicable. Statistical Analysis was performed using GraphPad Prism 8 software.

Results
The plasma creatinine dosage confirmed the renal insufficiency of the animals however, no changes were observed between 12 and 24 weeks of SNX (Table 1). Fibrosis in the kidney increased between 12 and 24 weeks of SNX as well as between their corresponding Sham (Table 1). Twenty-four weeks of SNX rats exhibited increased heart fibrosis in comparison to sham (Table 1). An increase in SAP was observed at 24 weeks of SNX in comparison to their Sham (Table 1). Cardiac remodeling between 12 and 24 weeks of SNX was observed through the increase in the left ventricle wall thickness (Table 1) (Fig. 1A). This was coupled with an increase in the expression of cardiac remodeling and protective-related genes FGF23 and GDF-15 (Fig. 1B,C). Diastolic function, as measured by E/A, remained unchanged in the model at both ages (Table 1). E deceleration time decreased at 24 weeks of SNX compared to their Sham (Table 1).

Conclusion
These preliminary results show a change in cardiac remodeling and function at 24 weeks of SNX compared to Sham. Between 12 and 24 weeks of SNX, changes in cardiac remodeling, namely hypertrophy of the posterior wall, can be observed. These changes were accompanied by an increase in FGF23 and GDF-15. As our model of cardio-renal syndrome has been characterized; we will turn our attention to the signaling involved in the establishment of cardiac fibrosis. This pre-clinical model will also make it possible to test new anti-fibrosis treatments.