Abstract 17100: Cardiotonic Steroids Promote Renal Fibrosis and Dysfunction via NaK-ATPase Profibrotic Signaling in Heart Failure
Introduction: Patients with heart failure such as those following myocardial infarction often experience progressive cardio-renal compromise (or “cardio-renal syndrome”), leading to recurrent hospitalizations and clinical deterioration. As our mechanistic understanding of cardio-renal syndrome is lacking, there are limited treatment options beyond contemporary therapies of neurohormonal blockade. Cardiotonic steroids (CTS) are Na/K-ATPase (NKA-α-1) ligands that are elevated in clinical and experimental heat failure, but their role in renal disease progression in this setting is unclear.
Hypothesis: We tested the hypothesis that CTS promote renal fibrosis and dysfunction in a process involving signaling through the NKA-α-1.
Methods/Results: First, we performed left anterior descending coronary artery ligation (LADx) on mice expressing wild type NKA-α-1 (WT), as well as mice expressing transgenic human NKA-α-1 (NKA-Tg), which renders them more sensitive to CTS. NKA-Tg mice demonstrated increased renal fibrosis 8 weeks after LADx vs WT (p<0.05). Next, we infused the CTS telocinobufagin (TCB, 4 weeks at 100 ug/Kg/day) or vehicle into WT and NKA-Tg mice. TCB infusion resulted in increased (> 5 fold) renal fibrosis in NKA-Tg vs WT mice (p<0.05). TCB also resulted in significant upregulation (>2 fold) of several pro-inflammatory molecules including IL17A, IL6, and CD70, as well as pro-fibrotic TGFB family members BMP6 and LEFTY2 in the kidneys of NKA-Tg vs WT mice (p<0.05).
Conclusions: These studies suggest that CTS mediate renal dysfunction in post-myocardial infarction heart failure through the NKA signaling pathway.
Author Disclosures: X. Fan: None. F.K. Khalaf: None. Y. Chen: None. A. Guggilam: None. A. Kleinhenz: None. J.B. Lingrel: None. J. Tian: None. W. Tang: None. D.J. Kennedy: None.
- © 2016 by American Heart Association, Inc.