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

International Journal of Molecular Sciences
David J KennedyW H Wilson Tang

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,...Continue Reading

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Citations

Jan 28, 2020·Pain Reports·Geissy I M C FeitosaKrishnamurti M Carvalho
Jul 9, 2020·International Journal of Molecular Sciences·Mishghan ZehraKomal Sodhi
Feb 6, 2020·Journal of the American Heart Association·Fatimah K KhalafDavid J Kennedy
Jun 12, 2020·Toxins·Robin C SuDavid J Kennedy
Oct 1, 2020·American Journal of Physiology. Cell Physiology·Jue ZhangYiliang Chen

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Methods Mentioned

BETA
urine collection
ELISA
protein assay
PCR
Assay
blood draw

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Qiagen cycler
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