Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism.
| Autor: | Harvey TW; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss., USA., Engel JE, Chade AR |
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| Jazyk: | angličtina |
| Zdroj: | American journal of nephrology [Am J Nephrol] 2016; Vol. 43 (2), pp. 74-84. Date of Electronic Publication: 2016 Mar 02. |
| DOI: | 10.1159/000444719 |
| Abstrakt: | Background: Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function. Methods: To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA). Results: Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes. Conclusion: ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD. (© 2016 S. Karger AG, Basel.) |
| Databáze: | MEDLINE |
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