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Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes

Yves Gorin1, Rita C Cavaglieri2, Khaled Khazim2

  • 1Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; gorin@uthscsa.edu.

American Journal of Physiology. Renal Physiology
|February 7, 2015
PubMed

Insights

The study shows that inhibiting Nox1/4 enzymes with GKT137831 protects kidneys in diabetic mice. This compound reduced kidney damage and markers of disease, suggesting it could treat type 1 diabetes-related kidney disease.

Area of Science:

  • Nephrology
  • Diabetology
  • Pharmacology

Background:

  • Diabetic nephropathy (DN) is a major complication of diabetes, linked to oxidative stress from NADPH oxidases (Nox).
  • Nox enzymes, particularly Nox1 and Nox4, are implicated in DN pathogenesis.
  • Targeting Nox enzymes offers a potential therapeutic strategy for DN.

Purpose of the Study:

  • To evaluate the renoprotective effects of the Nox1/Nox4 inhibitor GKT137831 in a mouse model of type 1 diabetes.
  • To assess the impact of GKT137831 on oxidative stress and kidney damage markers in established diabetic nephropathy.

Main Methods:

  • Diabetic OVE26 mice were treated with GKT137831 (10 or 40 mg/kg/day for 4 weeks).
  • Assessed NADPH oxidase activity, reactive oxygen species (ROS) production, and markers of kidney damage (fibronectin, collagen IV, glomerular hypertrophy, albuminuria, podocyte loss, macrophage infiltration).

Main Results:

  • GKT137831 effectively inhibited NADPH oxidase activity and ROS production in diabetic mouse kidneys.
  • Treatment reduced key DN markers, including fibronectin and type IV collagen expression.
  • Significant improvements were observed in glomerular hypertrophy, mesangial expansion, albuminuria, podocyte loss, and macrophage infiltration.

Conclusions:

  • Pharmacological inhibition of Nox1/4 by GKT137831 provides significant renoprotection in established diabetic nephropathy in type 1 diabetes.
  • The findings highlight the therapeutic potential of targeting Nox4 for treating diabetic kidney disease.
Keywords:
NADPH oxidaseNox1/Nox4 inhibitordiabetic nephropathy

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