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Abstract: SA-PO437

Cholesterol 25-Hydroxylase Protects Diabetic Kidney Disease by Regulating ADP Ribosylation Factor 4

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Zhang, Lu, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Fang, Zhengying, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Wei, Chengguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Liu, Ruijie, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Cholesterol 25-hydroxylase (CH25H) is a cholesterol hydroxylase which is actively involved in lipid metabolism. In kidney, CH25H predominantly expressed in endothelial cells and macrophages, which are renal resident cells and immune cells that have been proved of great importance in context of DKD progression. Intriguingly, the expression of CH25H is upregulated in diabetic mouse. In this study, we determined the effects of CH25H and its product 25HC in DKD.

Methods

C57BL/6J wild type (ch25h+/+/lepr+/+), ch25h KO (ch25h-/-/lepr+/+), diabetic (ch25h+/+/leprdb/db) and DKO (ch25h-/-/leprdb/db) were utilized in this study. The mice were sacrificed at the age of 24 weeks. C57BLKS/J male leprdb/+ and leprdb/db mice were used for 25HC treatment study. In vivo studies were conducted with human umbilical vein endothelial cells and immortalized human podocytes.

Results

CH25H predominantly expressed in glomerular and peritubular endothelial cells. Leprdb/db and STZ-induced diabetic mice have an elevated level of CH25H mRNA level in glomeruli. Global deletion of ch25h in Leprdb/db mice aggravated DKD, showing more albuminuria and worse glomerular hypertrophy and mesangial matrix deposition, and can be alleviated by 25HC treatment. In vivo studies revealed that 25HC binds to a GTP-binding protein Arf4, enhancing its activity by inhibiting the interaction between Arf4 and its GTPase-activating protein Asap1. Interesting, Asap1 expressed mostly in endothelial cells and its expression is increased in the diabetic kidney. In Golgi apparatus, Arf4 activity is required for maintaining essential protein transportation and cellular function, while in cytosol Arf4 inhibits the activity of Aldolase and accumulation of methylglyoxal, thereby preventing cells from death.

Conclusion

Lacking of CH25H aggravated DKD and can be rescued by exogenous supplement of its catalytic product 25HC. 25HC protects DKD by maintaining Arf4 activity via inhibiting Arf4 interaction with its GAP Asap1. Activated Arf4 is required for promoting protein transportation in golgi apparatus and suppressing methylglyoxal production in cytosol, thereby preventing cells from injuries.

Funding

  • NIDDK Support