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Notes:
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Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that “a disintegrin and metalloproteinase” (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce. We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF-α/ADAM17. Blockade of the TGF-α/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-α/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF-α/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF-α/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF-α/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action.
This work was supported by grants from the Instituto de
Salud Carlos III (ISCIIIRETIC REDINREN RD12, PI11/
01854, PI041/00041, PI13/00047, PIE13/00051, and PI0/
00072), Comunidad de Madrid (Fibroteam S2010/BMD-232;
CIFRA S2010/BMD-2378), Sociedad Española de Nefrología, European Network (FP7-HEALTH-2013-INNOVATION-1-
602422), and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to Alberto Ortiz. |
