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Abstract: TH-PO908

Deletion or Inhibition of ARF6 Improves Albuminuria in Type 2 Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Lin, Jamie, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Long, Jianyin, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Chang, Benny B., Baylor College of Medicine, Houston, Texas, United States
  • Galvan, Daniel L., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Green, Nathanael, Baylor College of Medicine, Houston, Texas, United States
  • Danesh, Farhad R., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Background

Podocytes are key glomerular cells that determine the progression of diabetic kidney disease (DKD), the leading cause of renal failure in the U.S. Small GTPase proteins regulate quintessential roles that govern cellular health – too much or too little GTPase activity can render podocytes susceptible to kidney injury. ADP-ribosylation factor 6 (ARF6), is a small GTPase protein that we previously showed is present in human and mouse podocytes and involved in podocyte response to in vivo glomerular injury models. Since ARF6 is involved in diverse cellular events (e.g. actin remodeling or endocytic trafficking) we hypothesized that hyperglycemia might result in alterations in ARF6 activity and contribute to the progression of DKD.

Methods

To investigate the in vivo role of ARF6 in diabetes, we generated an inducible podocyte-specific ARF6 knockout diabetic animal model. We also explored whether pharmacological intervention of ARF6 using an ARF6 inhibitor, Nav2729 (R&D Systems), might recapitulate the observations from our aforementioned transgenic animal model.

Results

High glucose cultured podocytes expressed significantly higher Arf6 mRNA and protein levels compared to normal glucose cultured podocytes. Isolated podocytes from diabetic (Leprdb/db) mice had increased ARF6 expression compared to control (Leprdb/+) mice. Furthermore, podocyte-specific ARF6KO mice had decreased urine albumin to creatinine ratio (UACR). To determine whether ARF6 might serve as a molecular target for pharmacological inhibition in DKD, diabetic mice were treated with an ARF6 inhibitor (NAV2729) or vehicle (DMSO) at 8 weeks of age. NAV2729-treated diabetic mice demonstrated significant improvement in the UACR compared to diabetic mice treated with vehicle suggesting a renal-protective effect of ARF6 inhibition.

Conclusion

These results suggest that ARF6 is an important protein involved in podocyte health and DKD. Inhibition of ARF6 might serve as a molecular target to prevent podocyte injury, albuminuria, and progressive renal functional decline.

Funding

  • NIDDK Support