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Original Research
Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
Zhonglin Chai, Tieqiao Wu, Aozhi Dai, Pacific Huynh, Frank Koentgen, Guy Krippner, Shuting Ren and Mark E. Cooper
Diabetes 2018 Nov; db180712. https://doi.org/10.2337/db18-0712
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Abstract

Targeting Cell Division Autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor-β in diabetic nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo if strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1, was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known “Cell Penetrating Peptide”, dose-dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a D-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes-associated increases in renal expression of genes involved in fibrotic and pro-inflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes associated molecular and pathological changes within the kidney. Specifically, CHA-061 attenuated significantly renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious and feasible approach to retard experimental diabetic nephropathy.

Footnotes

  • * Current address: Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville, Australia

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0712/-/DC1.

  • Received June 28, 2018.
  • Accepted October 29, 2018.
  • © 2018 by the American Diabetes Association.
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Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
Zhonglin Chai, Tieqiao Wu, Aozhi Dai, Pacific Huynh, Frank Koentgen, Guy Krippner, Shuting Ren, Mark E. Cooper
Diabetes Nov 2018, db180712; DOI: 10.2337/db18-0712

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Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
Zhonglin Chai, Tieqiao Wu, Aozhi Dai, Pacific Huynh, Frank Koentgen, Guy Krippner, Shuting Ren, Mark E. Cooper
Diabetes Nov 2018, db180712; DOI: 10.2337/db18-0712
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© 2019 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.