Targeting the CDA1/CDA1BP1 axis retards renal fibrosis in experimental diabetic nephropathy

Chai, Zhonglin, Wu, Tieqiao, Dai, Aozhi, Huynh, Pacific, Koentgen, Frank, Krippner, Guy, Ren, Shuting, and Cooper, Mark E. (2019) Targeting the CDA1/CDA1BP1 axis retards renal fibrosis in experimental diabetic nephropathy. Diabetes, 68 (2). pp. 395-408.

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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 whether strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1 (CDA1 binding protein 1), 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 the renal expression of genes involved in fibrotic and proinflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes-associated molecular and pathological changes within the kidney. Specifically, CHA-061 significantly attenuated 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.

Item ID: 57104
Item Type: Article (Research - C1)
ISSN: 1939-327X
Copyright Information: © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Funders: National Health and Medical Research Council of Australia (NHMRC).
Date Deposited: 13 Feb 2019 07:50
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110316 Pathology (excl Oral Pathology) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920104 Diabetes @ 100%
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