2. Academic Validation
  3. Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways

  • Int J Mol Sci. 2018 Aug 29;19(9):2566. doi: 10.3390/ijms19092566.
David J Kennedy 1,  Fatimah K Khalaf 2,  Brendan Sheehy 3,  Malory E Weber 4,  Brendan Agatisa-Boyle 5,  Julijana Conic 6,  Kayla Hauser 7,  Charles M Medert 8,  Kristen Westfall 9,  Philip Bucur 10,  Olga V Fedorova 11,  Alexei Y Bagrov 12,  W H Wilson Tang 13 14 15
Affiliations

Affiliations

  • 1 Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614, USA. David.Kennedy@UToledo.edu.
  • 2 Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614, USA. kareem.khalaf@rockets.utoledo.edu.
  • 3 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. bts21@case.edu.
  • 4 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. weberm9@ccf.org.
  • 5 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. bcaboyle@gmail.com.
  • 6 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. julijanaconic@gmail.com.
  • 7 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. kvmislick@gmail.com.
  • 8 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. c.maxmedert@gmail.com.
  • 9 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. WESTFAK@ccf.org.
  • 10 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. pb403014@ohio.edu.
  • 11 Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FedorovO@grc.nia.nih.gov.
  • 12 Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg 194223, Russia. aybagrov@gmail.com.
  • 13 Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. tangw@ccf.org.
  • 14 Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44106, USA. tangw@ccf.org.
  • 15 Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, USA. tangw@ccf.org.
PMID: 30158457 DOI: 10.3390/ijms19092566
Abstract

Cardiotonic Steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/-). Continuous TCB infusion results in increased proteinuria and Cystatin C in WT mice which are significantly attenuated in NKA α-1+/- mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

Keywords

Na+/K+-ATPase; cardiotonic steroids; fibrosis; kidney; signaling; telocinobufagin.

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