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Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease.

ABSTRACT: 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.

SUBMITTER: Perco P

PROVIDER: S-EPMC6629103 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease.

Perco Paul P Ju Wenjun W Kerschbaum Julia J Leierer Johannes J Menon Rajasree R Zhu Catherine C Kretzler Matthias M Mayer Gert G Rudnicki Michael M

JCI insight 20190620 12

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 w ...[more]

PMID: 31217356

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Project description:Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression.

Dataset Information

Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease.

Publications

Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease.

Similar Datasets

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