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Abstract: SA-OR068

Identification of Dicarbonyl and L-Xylulose Reductase (DCXR) as a Therapeutic Target in Human CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Perco, Paul, Medical University Innsbruck, Innsbruck, Austria
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Kerschbaum, Julia, Medical University Innsbruck, Innsbruck, Austria
  • Leierer, Johannes, Medical University Innsbruck, Innsbruck, Austria
  • Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
  • Zhu, Catherine, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Mayer, Gert J., Medical University Innsbruck, Innsbruck, Austria
  • Rudnicki, Michael, Medical University Innsbruck, Innsbruck, Austria
Background

Deregulation of renoprotective factors contributes to development and progression of chronic kidney disease (CKD).

Methods

Renal gene expression profiles of 197 renoprotective factors were analyzed in a cohort of 63 CKD patients. Median follow-up time was 6.9 years and association with disease outcome was assessed in Kaplan-Meier analysis and log-rank statistics. The multicenter NEPTUNE study served as validation cohort [n=225]. Associations with histological and clinical parameters were evaluated for the most significant renoprotective factor DCXR. The impact of SGLT2 inhibition on DCXR levels was furthermore assessed in human renal proximal tubular cells.

Results

DCXR was significantly associated with outcome in the discovery cohort (p-val < 0.0001) and the NEPTUNE validation cohort (p-val = 0.0001). Reduced expression of DCXR was significantly associated with the degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. DCXR expression was positively correlated to enzymes involved in dicarbonyl stress detoxification. The SGLT2 inhibitors canagliflozin and empagliflozin showing a beneficial effect on renal proximal tubular cells under diabetic stimuli enhanced DCXR gene expression up to 2.35 and 2.22 fold.

Conclusion

Lower expression of the renoprotective factor DCXR is associated with more severe disease and worse outcome in human chronic kidney disease.

Dicarbonyl and L-xylulose reductase (DCXR) was significantly associated with disease outcome in the discovery cohort (p-value < 0.0001) as well as in the NEPTUNE validation cohort (p-value = 0.00012) in Kaplan Meier analysis and log-rank test statistics.

Funding

  • Government Support - Non-U.S.