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Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy.

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2019

Diabetes 2019 Feb;68(2):395-408. doi: 10.2337/db18-0712. Epub 2018 Nov 13.

Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy.

Z Chai;T Wu;A Dai;P Huynh;F Koentgen;G Krippner;S Ren;ME Cooper

Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia. Ozgene Pty Ltd., Bentley, Western Australia, Australia. Department of Commercialization, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China.

Service type: Knockout mice

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.

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