Chronic kidney disease induced by an adenine rich diet upregulates integrin linked kinase (ILK) and its depletion prevents the disease progression |
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Authors: | Sergio de Frutos Alicia Luengo Andrea García-Jérez Marco Hatem-Vaquero Mercedes Griera Francisco OValle Manuel Rodríguez–Puyol Diego Rodríguez–Puyol Laura Calleros |
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Institution: | 1. Department of Systems Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain;2. IRSIN, IRYCIS (Instituto de Salud Carlos III), Madrid, Spain;3. REDinREN (Instituto de Salud Carlos III), Madrid, Spain;4. Department of Medicine, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain;5. Department of Nephrology Section and Research Foundation, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain;6. Departamento de Anatomía Patológica e Historia de la Ciencia, Universidad de Granada, Granada, Spain |
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Abstract: | Kidney fibrosis is one of the main pathological findings of progressive chronic kidney disease (CKD) although the pathogenesis of renal scar formation remains incompletely explained. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix (ECM) and intracellular signaling pathways, is involved in several pathophysiological processes during renal damage. However, ILK contribution in the CKD progress remains to be fully elucidated. In the present work, we studied 1) the renal functional and structural consequences of CKD genesis and progression when ILK is depleted and 2) the potential of ILK depletion as a therapeutic approach to delay CKD progression. We induced an experimental CKD model, based on an adenine-supplemented diet on adult wild-type (WT) and ILK-depleted mice, with a tubulointerstitial damage profile resembling that is observed in human CKD. The adenine diet induced in WT mice a progressive increase in plasma creatinine and urea concentrations. In the renal cortex it was also observed tubular damage, interstitial fibrosis and progressive increased ECM components, pro-inflammatory and chemo-attractant cytokines, EMT markers and TGF-β1 expressions. These observations were highly correlated to a simultaneous increase of ILK expression and activity. In adenine-fed transgenic ILK-depleted mice, all these changes were prevented. Additionally, we evaluated the potential role of ILK depletion to be applied after the disease induction, as an effective approach to interventions in human CKD subjects. In this scenario, two weeks after the establishment of adenine-induced CKD, ILK was abrogated in WT mice and stabilized renal damage, avoiding CKD progression. We propose ILK to be a potential target to delay renal disease progression. |
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Keywords: | Corresponding author at: Department of Systems Biology Physiology Unit Facultad de Medicina Universidad de Alcalá Campus Universitario s/n Alcalá de Henares 28871 Madrid Spain Chronic renal disease Integrin-linked kinase Tubulointerstitial damage Fibrosis Epithelial-to-mesenchymal transition Inflammation |
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