The renal phenotype of allopurinol-treated HPRT-deficient mouse
| العنوان: | The renal phenotype of allopurinol-treated HPRT-deficient mouse |
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| المؤلفون: | Marialaura Marchetti, Riccardo Percudani, Cristina Zennaro, Federica Tonon, Alessandro Corbelli, Luca Ronda, Paola Zarattini, Gianluca Paredi, Milan Clai, Maria Pia Rastaldi, Michele Carraro |
| المساهمون: | Zennaro, Cristina, Tonon, Federica, Zarattini, Paola, Clai, Milan, Corbelli, Alessandro, Carraro, Michele, Marchetti, Marialaura, Ronda, Luca, Paredi, Gianluca, Pia Rastaldi, Maria, Percudani, Riccardo |
| المصدر: | PLoS ONE, Vol 12, Iss 3, p e0173512 (2017) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Hypoxanthine Phosphoribosyltransferase, Lesch-Nyhan Syndrome, LESCH-NYHAN-SYNDROME, 030232 urology & nephrology, lcsh:Medicine, Biochemistry, DISEASE, Mice, chemistry.chemical_compound, 0302 clinical medicine, Medicine and Health Sciences, XANTHINE OXIDOREDUCTASE, Renal Failure, Polarized Light Microscopy, lcsh:Science, Hypoxanthine, Mice, Knockout, Liquid Chromatography, Microscopy, Nephritis, Multidisciplinary, Organic Compounds, Chromatographic Techniques, Light Microscopy, Lipids, Chemistry, Nephrology, Physical Sciences, CLASSICAL XANTHINURIA, Anatomy, Research Article, medicine.drug, Xanthine Oxidase, Materials by Structure, NEPHROPATHY, Allopurinol, Materials Science, URIC-ACID, Biology, Research and Analysis Methods, PURINE NUCLEOSIDE PHOSPHORYLASE, Xanthine, Crystals, Nephropathy, 03 medical and health sciences, medicine, Animals, Xanthine oxidase, MESENCHYMAL TRANSITION, Organic Chemistry, lcsh:R, Chemical Compounds, Biology and Life Sciences, Kidneys, Renal System, medicine.disease, GENE, Molecular biology, High Performance Liquid Chromatography, Uric Acid, 030104 developmental biology, chemistry, Purines, URATE-OXIDASE, Uric acid, lcsh:Q, Lesch–Nyhan syndrome, Acids |
| الوصف: | Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice. Allopurinol was administered in the drinking water of E12-E14 pregnant mothers at dosages of 150 or 75 mu g/ml, and mice sacrificed after weaning. The drug was well tolerated by wild-type animals and heterozygous HPRT+/- mice. Instead, a profound alteration of the renal function was observed in the HPRT-/- model. Increased hypoxanthine and xanthine concentrations were found in the blood. The kidneys showed a yellowish appearance, diffuse interstitial nephritis, with dilated tubules, inflammatory and fibrotic changes of the interstitium. There were numerous xanthine tubular crystals, as determined by HPLC analysis. Oil red O staining demonstrated lipid accumulation in the same location of xanthine deposits. mRNA analysis showed increased expression of adipogenesis-related molecules as well as profibrotic and proinflammatory pathways. Immunostaining showed numerous monocyte-macrophages and overexpression of alpha-smooth muscle actin in the tubulointerstitium. In vitro, addition of xanthine to tubular cells caused diffuse oil red O positivity and modification of the cell phenotype, with loss of epithelial features and appearance of mesenchymal characteristics, similarly to what was observed in vivo. Our results indicate that in the absence of HPRT, blockade of XO by allopurinol causes rapidly developing renal failure due to xanthine deposition within the mouse kidney. Xanthine seems to be directly involved in promoting lipid accumulation and subsequent phenotype changes of tubular cells, with activation of inflammation and fibrosis. |
| وصف الملف: | ELETTRONICO |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::06f70904dd8133e2e8899988454ec61bTest https://doi.org/10.1371/journal.pone.0173512Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....06f70904dd8133e2e8899988454ec61b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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