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Abstract: FR-OR057

Development of a Peptide Inhibitor of a Novel Target to Retard Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Chai, Zhonglin, Monash University Central Clinical School, Melbourne, Victoria, Australia
  • Cooper, Mark E., Monash University, Melbourne, Victoria, Australia
Background

Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide, and remains suboptimally treated medically. A large body of compelling data from our group have demonstrated a critical role of CDA1 in DN and validated CDA1/CDA1BP1 interaction as a promising target to retard diabetic nephropathy. We have developed a prototype inhibitor, CHA-061, to target this novel axis.

Methods

This study focuses on the assessment of CHA-061 for its efficacy to attenuate parameters relevant to renal fibrosis in two models of diabetes. The first model is an insulin deficient model using streptozotocin (STZ)-induced diabetes in ApoE KO mice, a model relevant to type 1 diabetes. The second is a type 2 diabetes model using db/db mice which initially become obese and subsequently diabetic as a result of the leptin receptor mutation. Both non-diabetic control and diabetic mice with established DN after diabetes was developed for 10 weeks were randomly allocated to receive either vehicle or CHA-061 treatment (10 mg/kg IP injections twice a week) for 10 weeks.

Results

The analysis of kidney tissues showed that, in the vehicle treated ApoE KO mice, diabetes was associated with >2-fold increase in gene expression of sclerotic molecules such as collagens I and III as well as proinflammatory genes such as TNFα and MCP1. Immunohistochemical staining of collagen III was increased >10-fold and the glomerulosclerosis index (GSI) as assessed by PAS staining was increased >2-fold in diabetic ApoE KO mice. These parameters were significantly attenuated in CHA-061 treated diabetic ApoE KO mice. Similarly, CDA1 expression levels were increased ~2-fold in diabetic db/db mice accompanied by >2-fold increase in gene expression of sclerotic molecules such as CTGF, fibronectin, collagens I, III and IV when compared to the non-diabetic dbh mice. CHA-061 treatment reduced these parameters in the diabetic db/db mice to levels similar to those in the non-diabetic controls. These results were consistent with our previous target validation data using CDA1 KO and CDA1BP1 KO mouse strains.

Conclusion

Taken together, the current study has demonstrated the efficacy and feasibility to pharmacologically target the novel CDA1/CDA1BP1 axis to retard nephropathy in both type 1 and type 2 diabetes by targeting not only fibrotic but also proinflammatory pathways.

Funding

  • Government Support - Non-U.S.