Abstract: TH-PO676

Function of NADPH Oxidase in Diabetic Nephropathy and Development of Its Inhibitor as a Therapeutic Candidate

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress

Authors

  • Lee, Sae rom, Ewha Womans University , Seoul, Korea (the Republic of)
  • An, Eunjung, Ewha Womans University , Seoul, Korea (the Republic of)
  • Bae, Yun soo, Ewha Womans University , Seoul, Korea (the Republic of)
Background

Substantial evidence has indicated that transient reactive oxygen species (ROS) can be produced by receptor-mediated biochemical processes, although ROS including superoxide anion and hydrogen peroxide (H2O2) are thought to be by-products of aerobic respiration damaging effects on DNA, protein, and lipid. ROS generation in cell signaling has been extensively studied in terms of NADPH oxidase (gp91phox) in phagocytic cells. However, after identification of the homologs of gp91phox (Nox1, Nox3-5, Duox1-2) from non-phagocytic cells, the function of the generated ROS has been extended into an understanding of various cellular events, including cell growth, differentiation, apoptosis, and inflammation responses. We show the effect of a novel pan-NOX-inhibitor, EWHA-18278, on diabetic nephropathy in type 2 diabetic mice.

Methods

Six-week-old male diabetic db/db mice was treated with EWHA-18278(60mpk) per day and sacrificed after 12 weeks. The effect of EHWA-18278 on oxidative markers such as 8-isoprostane in plasma or urine was measured. Furthermore, EHWA-18278 effect on renal function was investigated by urinary albumin excretion and creatinine clearance and PAS-staining, alpha-SMA histologically.

Results

EWHA-18278 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the EWHA-18278 group compared to diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. EWHA-18278 decreased urinary albumin excretion and preserved creatinine clearance. In diabetic kidneys, EWHA-18278 significantly improved mesangial expansion, but GKT137831 did not. Additionally, F4/80 infiltration in the adipose tissue and kidney decreased with EWHA-18278 treatment.

Conclusion

In conclusion, our findings provide evidence that pan-Nox inhibition by EWHA-18278 may have greater renoprotective potential than does GKT137831 in diabetic nephropathy. These findings suggest that EWHA-18278 may be a useful new therapeutic agent in treating type II diabetes and diabetic nephropathy.