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Molecular Pathophysiology of Primary Hyperuricemia and Gout
Bohatá, Jana ; Stibůrková, Blanka (advisor) ; Hrnčíř, Zbyněk (referee) ; Friedecký, David (referee)
Primary hyperuricemia, as a condition of elevated serum uric acid levels, is caused by various factors and necessarily precedes a form of inflammatory arthritis referred to as gout. Uric acid is the end product of purine catabolism and requires specialized proteins for its transport. Pathogenic variants in the genes for these transport proteins can have a major negative impact on their function, thereby affecting the resulting serum uric acid levels. However, chronically elevated uric acid levels are not the only predisposition to the development of gout. Other factors, such as epigenetic mechanisms or genetic predispositions to inflammatory conditions caused by immune dysregulation, are likely to play a role in disease progression. The aim of the study was to analyse damaging variants in genes for important urate transporters ABCG2, SLC22A12 and SLC2A9, which may cause impaired excretion or reabsorption of uric acid and thus contribute to the development of primary hyperuricemia and gout, or rare hereditary renal hypouricemia. We also focused on circulating miRNAs in the plasma of patients with primary hyperuricemia, gout and gout attack. We identified and functionally characterized over ten rare nonsynonymous variants in the ABCG2 gene. Most of these variants had a negative impact on protein...
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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea ; Krylov, Vladimír (advisor) ; Novotný, Jiří (referee) ; Ježek, Petr (referee)
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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In vitro study of drug-drug interactions of HIV protease inhibitor darunavir on efflux ABC transporters
Bezděková, Dominika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Dominika Bezděková Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: IN VITRO STUDY OF DRUG-DRUG INTERACTIONS OF HIV PROTEASE INHIBITOR DARUNAVIR ON EFFLUX ABC TRANSPORTERS Abstract: Darunavir is a drug used in the therapy of HIV belonging to the group of protease inhibitors. These protease inhibitors are used as a part of the combination antiretroviral therapy. For the increase of bioavailability, darunavir is always used in combination with ritonavir or cobicistat. As the CYP3A4 and ABCB1 (P-glycoprotein) transporter substrate, darunavir is a drug with a high potential to drug interactions. Considering the amount of adverse effects that can be caused by darunavir, it is necessary to know these drug interactions for the safety of therapy. Inhibition of the intestinal ABCB1 by the co-administrated drugs could also lead to the increased bioavailability of darunavir and to reduction of frequency of administration leading to a cheaper therapy. This thesis studies the drug-drug interactions of darunavir with in vitro methods using two cell lines - MDCKII and Caco-2 cells. The results from the transport of darunavir across the MDCKII cell monolayer indicates that darunavir is a ABCB1...
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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea ; Krylov, Vladimír (advisor) ; Novotný, Jiří (referee) ; Ježek, Petr (referee)
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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