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.
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.
Log in using your username and password
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.