Wnt/β-catenin signalling mediates cardiac hypertrophy in type 4 cardiorenal syndrome

Aim: Cardiorenal syndrome type 4 (CRS4) is characterized by the condition that chronic kidney disease (CKD) causes sustainable injury to heart. This study focuses on exploring the mechanism underlying CRS4 and potential treatment for CRS4. Methods: In the present study, Sprague Dawley (SD) rats were subjected to 5/6 subtotal nephrectomy (5/6NX) for generating animal model of CKD. Cardiac hypertrophy, kidney injury, Wnt/beta-catenin signalling and serum TNF-alpha were tested at eighth week after 5/6NX. Results: Cardiac hypertrophy and kidney injury were prominent and accompanied by Wnt/beta-catenin activation in rats at eighth week after 5/6NX. Blockade of Wnt/beta-catenin by ICG-001 reduced 5/6NX-stimulated fibronectin and podocalyxin in remnant kidney. Interestingly, ICG-001 also inhibited hypertrophic markers beta-MHC and alpha-actin and reduced cardiac hypertrophy. In addition, TNF-alpha, as a systemic inflammation factor in blood circulation, was suggested to connect CKD to cardiac hypertrophy. It was demonstrated in vitro and in vivo studies that ICG-001 is sufficient to counteract TNF-alpha-induced cardiac hypertrophy by sequestration of beta-catenin. Conclusion: These results demonstrate that Wnt/beta-catenin to be a unified pathogenic pathway of heart disorder and kidney disease in CRS4. Based on that, Wnt/beta-catenin signalling could be a target of promising therapy for protecting both heart and kidney organs in CRS4.