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Association of DCXR with members of the formation of xylulosephosphate pathway and the dicarbonyl stress detoxification cascade. DCXR is member of the formation of xylulosephosphate pathway. Figure 8 DCXR in the formation of xylulosephosphate pathway and the link to dicarbonyl stress detoxification. Schematic representations of the formation of xylulosephosphate pathway and key players in detoxification of dicarbonyl stress.
Correlation coefficients to DCXR based on mRNA gene expression in the 4 renal tubular transcriptomics data sets used in this study are provided for key pathway members.
Significant positive and negative correlations are highlighted in red and blue, respectively. We furthermore determined correlations of DCXR expression with key enzymes involved in dicarbonyl stress detoxification. We investigated the effect of the sodium glucose cotransporter-2 SGLT2 inhibitor canagliflozin on DCXR expression in human renal proximal tubular cells HK2 that have been stimulated with high glucose.
The authors of this study have determined gene expression profiles in 2 renal proximal tubular cells RPTECs studying the effect of the 2 SGLT2 inhibitors canagliflozin and empagliflozin. DCXR expression levels increased 1.
Diamonds indicate group mean expression values. Discussion This is, to our knowledge, the first study reporting on the association with disease progression of the renoprotective factor DCXR in the context of human CKD.
A number of clinical parameters has been reported to be associated with the course of disease development in CKD patients, including impaired renal function itself, hypertension, as well as the degree of proteinuria 9 — Other risk factors associated with a worse prognosis are presence of cardiovascular disease or diabetes, black race, or being male Our discovery cohort of 63 CKD patients seems to be representative, with significant associations to disease outcome observed for sex, baseline eGFR, and type of diagnosis.
We decided to investigate this rather heterogeneous CKD patient population with different CKD diagnoses represented to increase our chances of detecting common renoprotective mechanisms and factors of general utility. In addition to clinical parameters, a number of molecular biomarkers have been discovered, with the majority being elevated in the diseased state 13 — In this work, we were particularly interested in molecules with renoprotective properties instead of damaging potential.
Of a previously published set of proteins with renoprotective potential 6 , 6 are identified as predictors of CKD outcome in our discovery cohort. The focus of all further analyses and validation in the current study were subsequently on the sixth renoprotective factor, namely DCXR, for which no human data in the context of CKD disease progression is available. DCXR is a member of the formation of xylulosephosphate pathway with the main function of converting L-xylulose to xylitol.
Deficiency in DCXR is linked to pentosuria, a condition characterized by high L-xylulose levels in urine We found strong positive correlations of tubular DCXR expression to other members of the formation of xylulosephosphate pathway in our study. Based on these data and consolidated literature information, we speculate that DCXR might offer a complementary way of counterbalancing dicarbonyl stress in human renal tubular cells Figure Tubular DCXR converts L-xylulose to xylitol with high urinary L-xylulose levels being characteristic for the benign condition of pentosuria.
The first clinical trials NCT testing GLO1 inducers in the context of diabetes and associated vascular complications have already shown promising results 33 , Induction of DCXR might, therefore, provide an alternative way of counterbalancing dicarbonyl stress to reduce generation of AGEs with a final beneficial effect on kidney function.
The major driver of this significant association with disease outcome, in both the discovery and the validation cohorts, are patients in the first tertile of DCXR expression levels, i. The most significant association was found in the group of FSGS patients the largest subgroup with 68 subjects.
FSGS is one of the disease entities showing a large variance in the outcome parameter. The smaller sample sizes for the MN patient subgroup, as well as for the patient subgroup with other diseases, may have weakened the association with disease outcome.
The association of DCXR expression with clinical outcome and histological damage suggests that DCXR is a marker mechanistically linked to renal damage and may, therefore, serve as a novel molecule for therapeutic intervention. DCXR was also found to be negatively associated with cortical interstitial fractional volume by Nair and colleagues In addition, calcineurin inhibitor treatment after renal transplantation had a detrimental effect on DCXR gene expression based on a microarray study by Maluf and colleagues DCXR protein concentration was also found to be upregulated around 2-fold in glomerular tissue from patients with diabetes mellitus who were being protected from development of diabetic kidney disease Very recently, DCXR was found in a proteomics study in a rat model to be downregulated in rat myocardium during development of type 2 diabetes SGLT2 inhibitors delay kidney function decline and have beneficial effect on cardiovascular outcome, although the exact underlying mechanisms are not fully understood 40 — Canagliflozin, in our study, significantly upregulated DCXR expression levels by 1.
In a recently published transcriptomics data set the effect of the two studied SGLT2 inhibitors canagliflozin and empagliflozin was even higher, resulting in DCXR expression increases of up to 2. DCXR itself or associated metabolites in the mechanistic context of DCXR deregulation might hold the potential to serve as predictive markers for SGLT2 inhibitors, which, however, needs to be determined in subsequent studies.
Future mechanistic studies may also shed light on the link between SGLT2 inhibitors and dicarbonyl stress. Despite these congruent findings across different cohorts, this study has its limitations. Due to this composition of the discovery cohort, we might have missed some promising renoprotective factors with prognostic potential in specific CKD entities.
We also only focused on those renoprotective factors being significantly downregulated in progressive CKD in this study. Logical next steps in future studies are a to determine the potential of DCXR and mechanistically linked metabolites in body fluids as noninvasive prognostic biomarkers for CKD progression and b to identify endogenous upstream regulators and compounds capable of inducing DCXR expression.
There is evidence that DCXR is detectable on the protein level in urine samples based on a mass spectrometry study by Adachi and colleagues in which they characterized the human urinary proteome Methods Generating the set of renoprotective factors. In this study, we focused on a set of proteins previously reported to have renoprotective potential 6. Associations with renoprotection of these 4 proteins were not based on GeneRIFs but evidence from the literature 45 — The discovery CKD patient cohort.
We determined the association with disease progression of renoprotective factor gene expression by reanalyzing a retrospective cohort of 63 patients with various CKD diagnoses.
Follow-up data from this patient cohort were updated in Q2 Patients with a minimum follow-up time of 6 months who reached ESRD or experienced doubling of serum creatinine during the follow-up period were defined as progressive.
Patients who did not develop ESRD or doubling of serum creatinine during follow-up with a minimum available follow-up time of 12 months were defined as stable. Clinical data from the last available follow-up visit were recorded in stable patients.
For patients from the progressive group who started dialysis treatment, the last UPCR and serum creatinine values before initiation of dialysis were recorded.
Information on the degree of histological damage recorded by a pathologist was available for 55 patients. Gene expression analysis of renoprotective factors in the discovery cohort.
Preprocessing consisted of background correction, quantile normalization and summarization of probes with the same sequence spotted multiple times on the array. DCXR expression analysis in renal compartments. DCXR mRNA expression and protein abundance levels in renal compartments were investigated using data from kidney donors with normal renal function from a published gene expression study by Lindenmeyer and colleagues 7 , as well as data from the Human Protein Atlas The first study published by Lee and colleagues provided comprehensive gene expression profiles in glomeruli and each of the 14 renal tubule segments after renal tubule microdissection from male Sprague-Dawley rats The second expression study included 3 single-cell RNA-Seq data sets using adult tumor nephrectomy samples specifically harvested for single-cell analysis using 10X Genomics methodology DCXR expression in renal cortex and tubulointerstitial compartments was compared between CKD patients and healthy controls in data from Woroniecka et al.
NEPTUNE is a multicenter prospective cohort study of patients with proteinuric glomerular disease for which comprehensive clinical and molecular phenotyping data was collected at 21 sites The degree of interstitial fibrosis and tubular atrophy was assessed by at least 5 independent pathologists and given as the average percentage of obtained scores 56 , Time-to-event analysis was also performed for individual CKD diagnosis groups.
Univariate Cox regression analysis was subsequently used to determine hazard ratios for molecular, clinical, and histological parameters. Gene expression data used in this study are available within the Nephroseq database. Correlation analysis to assess the mechanistic context of DCXR in human renal tubuli. The correlation of DCXR mRNA expression to other pathway members was determined in the 4 human renal tubular gene expression data sets by Nakagawa et al.
We furthermore investigated DCXR correlations based on tubular mRNA expression patterns to key members of the dicarbonyl stress detoxification cascade. Cells were serum deprived for 24 hours after grown to confluence. Cells were treated with 0. Materials for microarray experiments were downloadd from Agilent Technologies Inc.
For each sample, ng total RNA was used. Preprocessing of transcriptomics data, including background correction, normalization, filtering, and summarization of identical sequence probes, was done using the limma R statistical package.