Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways
| Autor: | W.H. Wilson Tang, Fatimah K Khalaf, Julijana Conic, Olga V. Fedorova, Kristen Westfall, Kayla Hauser, Malory E. Weber, David J Kennedy, Alexei Y. Bagrov, Brendan Agatisa-Boyle, Philip Bucur, Brendan Sheehy, Charles M. Medert |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Swine Na+/K+-ATPase medicine.medical_treatment 030204 cardiovascular system & hematology lcsh:Chemistry Mice 0302 clinical medicine Fibrosis Phosphorylation Ouabain lcsh:QH301-705.5 Spectroscopy Kidney biology Chemistry General Medicine respiratory system 3. Good health Computer Science Applications medicine.anatomical_structure Kidney Diseases Sodium-Potassium-Exchanging ATPase signaling Signal Transduction medicine.medical_specialty kidney telocinobufagin MAP Kinase Signaling System Article Catalysis Cell Line Inorganic Chemistry 03 medical and health sciences Internal medicine medicine Renal fibrosis Animals Physical and Theoretical Chemistry Molecular Biology Glycogen Synthase Kinase 3 beta Growth factor Organic Chemistry fibrosis Transforming growth factor beta medicine.disease nervous system diseases Bufanolides CTGF 030104 developmental biology Endocrinology Cystatin C lcsh:Biology (General) lcsh:QD1-999 cardiotonic steroids biology.protein |
| Zdroj: | International Journal of Molecular Sciences, Vol 19, Iss 9, p 2566 (2018) International Journal of Molecular Sciences Volume 19 Issue 9 |
| ISSN: | 1422-0067 |
| Popis: | 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 &alpha 1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µ g/g/day) or a vehicle into mice expressing wild-type (WT) NKA &alpha 1, as well as mice with a genetic reduction (~40%) of NKA &alpha 1 (NKA &alpha 1+/&minus ). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA &alpha 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. |
| Databáze: | OpenAIRE |
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