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Abstract: FR-PO449

Cathepsin D: A Potential Biomarker for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Drel, Viktor, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Vaisar, Tomas, University of Washington, Seattle, Washington, United States
  • Kim, Jiwan John, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Valo, Erkka A., Folkhälsan Research Center, Helsinki, Finland
  • Zhang, Jing, University of California San Diego, La Jolla, California, United States
  • Ahluwalia, Tarunveer S., Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Snell-Bergeon, Janet, University of Colorado Denver , Aurora, Colorado, United States
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Groop, Per-Henrik, Folkhälsan Research Center, Helsinki, Finland
  • Natarajan, Loki, University of California San Diego, La Jolla, California, United States
  • Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States
  • de Boer, Ian H., University of Washington, Seattle, Washington, United States
  • Darshi, Manjula, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States
Background

Cathepsins are lysosomal proteases that play important roles in a wide range of physiological and pathological processes. Recent studies have suggested that dysregulation of cathepsin D (Cat D) can lead to development of fibrosis and induce apoptosis in the podocytes and tubular cells in acute kidney injury murine models. In the current study we analyzed if changes in Cat D are associated with the development and progression of diabetic kidney disease (DKD) in type I diabetic mouse models and in humans.

Methods

Cat D protein levels in urine were measured by liquid-chromatography mass spectroscopy in four diverse cohorts (CACTI, EDC, Finn-Diane, and Steno) with long-standing type I diabetes and normal kidney function (eGFR≥60ml/min/1.73m2). Subjects were classified into slow decliners/controls with eGFR decline ≤1ml/min/1.73m2/yr or rapid progressors/cases with eGFR decline of ≥3ml/min/1.73m2/yr. Cat D activity in urine samples of patients with established kidney disease (eGFR<40ml/min/1.73m2) and in type 1 DKD mouse model (Akita) was measured biochemically. Immunohistochemistry in mouse kidney tissues were performed with FFPE embedded kidney sections.

Results

Baseline mean eGFR and median ACR in controls (n=351) and cases (n=270) were 91.97 (sd 18.68) and 9.44 (IQR 30), and 98.37 (sd 25.44) and 33.49 (IQR 283.01), respectively. Cat D protein levels in urine were significantly elevated in cases as compared to controls [mean 1.18 au (1.07-1.3) in controls vs 1.56 au (1.37 to 1.57) in cases, p<001, FDR q=0.01). Immunohistochemical analysis identified predominant localization of Cat D to tubules in akita kidney sections and increased as compared to controls. Cat D activity was significantly elevated in urine (p<0.001) samples of of akita mice (n=6 each WT and akita, p<0.001) and in patients with established DKD (n=10 each control and DKD, p<0.0001). Cat D activity also correlated significantly (R2: 0.855, p<0.0001) with albumin/creatinine in akita mouse urine.

Conclusion

The current data indicate that Cathepsin D may play vital role in the pathogenesis of diabetic kidney disease and its level as well as activity in urine can serve as biomarker of the diabetic nephropathy.

Funding

  • Private Foundation Support