Abstract 15509: Granulocyte Macrophage Colony-Stimulating Factor from the Kidneys is Essential for the Development of Heart Failure Through the Heart-Brain-Kidney Interaction
The molecular mechanisms underlying the cardiorenal interaction are poorly understood. We previously showed that a transcription factor, KLF5, present in renal collecting duct epithelial cell controls the responses to renal injury by regulating macrophage accumulation and activation. We hypothesized that the kidneys regulate the development of heart failure via KLF5. We generated kidney-specific Klf5 knockout mice and evaluated the role of the kidneys on heart failure induced by transverse aorta constriction (TAC) in these mice compared to wild-type mice. Interestingly, the kidney-specific Klf5 knockout mice developed heart failure and cardiac death by decreased cardiac function, but not by renal dysfunction, when they underwent TAC. In these mice, cardiac hypertrophy and fibrosis were markedly suppressed compared with wild-type mice, thus indicating that the kidney-specific Klf5 deletion severely compromised the cardiac responses to pressure overload. The number of alternative activated macrophages in the heart was markedly increased after TAC in wild type mice. However, this induction was almost completely absent in the kidney-specific Klf5 knockout mice. In addition, wild type mice with macrophage depletion by clodronate liposome administration also developed severe heart failure. These results indicated that cardiac macrophages have protective effects against heart failure, and that they are regulated by the kidneys. We also found granulocyte macrophage colony-stimulating factor (GM-CSF) to be a downstream gene of Klf5 in the kidneys. The administration of a neutralizing antibody for GM-CSF in wild type mice with TAC resulted in severe heart failure. On the other hand, replacement therapy using GM-CSF in kidney-specific Klf5 knockout mice successfully prevented cardiac macrophage insufficiency, cardiac dysfunction and death after TAC. Moreover, sympathetic nerve ablation around the bilateral renal arteries also led to the development of insufficient GM-CSF production by KLF5 after TAC. In conclusion, cardiac macrophage activation, which is regulated by the serum GM-CSF produced by the kidneys via the heart-brain-sympathetic nerve activation-kidney KLF5 pathway, is essential for the adaptive response to cardiac stress.
- © 2012 by American Heart Association, Inc.