Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease
An imbalance of nephroprotective factors and renal damaging molecules contributes to development and progression of chronic kidney disease (CKD). We investigated associations of renoprotective factor gene expression patterns with CKD severity and outcome. Gene expression profiles of 197 previously reported renoprotective factors were analyzed in a discovery cohort in renal biopsies of 63 CKD patients. Downregulation of dicarbonyl and L-xylulose reductase (DCXR) showed the strongest association with disease progression. This significant association was validated in an independent set of 225 patients with nephrotic syndrome from the multicenter NEPTUNE cohort. Reduced expression of DCXR was significantly associated with degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. DCXR downregulation in CKD was confirmed in 3 publicly available transcriptomics data sets in the context of CKD. Expression of DCXR showed positive correlations to enzymes that are involved in dicarbonyl stress detoxification based on transcriptomics profiles. The sodium glucose cotransporter-2 (SGLT2) inhibitors canagliflozin and empagliflozin showed a beneficial effect on renal proximal tubular cells under diabetic stimuli-enhanced DCXR gene expression. In summary, lower expression of the renoprotective factor DCXR in renal tissue is associated with more severe disease and worse outcome in human CKD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
JCI insight - 4(2019), 12 vom: 20. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Perco, Paul [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.08.2020 Date Revised 12.10.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.128120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM298335344 |
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| 100 | 1 | |a Perco, Paul |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease |
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| 500 | |a Date Revised 12.10.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a An imbalance of nephroprotective factors and renal damaging molecules contributes to development and progression of chronic kidney disease (CKD). We investigated associations of renoprotective factor gene expression patterns with CKD severity and outcome. Gene expression profiles of 197 previously reported renoprotective factors were analyzed in a discovery cohort in renal biopsies of 63 CKD patients. Downregulation of dicarbonyl and L-xylulose reductase (DCXR) showed the strongest association with disease progression. This significant association was validated in an independent set of 225 patients with nephrotic syndrome from the multicenter NEPTUNE cohort. Reduced expression of DCXR was significantly associated with degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. DCXR downregulation in CKD was confirmed in 3 publicly available transcriptomics data sets in the context of CKD. Expression of DCXR showed positive correlations to enzymes that are involved in dicarbonyl stress detoxification based on transcriptomics profiles. The sodium glucose cotransporter-2 (SGLT2) inhibitors canagliflozin and empagliflozin showed a beneficial effect on renal proximal tubular cells under diabetic stimuli-enhanced DCXR gene expression. In summary, lower expression of the renoprotective factor DCXR in renal tissue is associated with more severe disease and worse outcome in human CKD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Chronic kidney disease | |
| 650 | 4 | |a Expression profiling | |
| 650 | 4 | |a Molecular pathology | |
| 650 | 4 | |a Nephrology | |
| 650 | 7 | |a Protective Agents |2 NLM | |
| 650 | 7 | |a Sugar Alcohol Dehydrogenases |2 NLM | |
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| 650 | 7 | |a L-xylulose reductase |2 NLM | |
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| 700 | 1 | |a Ju, Wenjun |e verfasserin |4 aut | |
| 700 | 1 | |a Kerschbaum, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Leierer, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Menon, Rajasree |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Kretzler, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Mayer, Gert |e verfasserin |4 aut | |
| 700 | 1 | |a Rudnicki, Michael |e verfasserin |4 aut | |
| 700 | 0 | |a Nephrotic Syndrome Study Network (NEPTUNE) |e verfasserin |4 aut | |
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