Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy

Diabetes. 2011 Nov;60(11):3055-66. doi: 10.2337/db11-0807.

Abstract

Objective: To determine whether dietary compounds targeting NFE2-related factor 2 (Nrf2) activation can be used to attenuate renal damage and preserve renal function during the course of streptozotocin (STZ)-induced diabetic nephropathy.

Research design and methods: Diabetes was induced in Nrf2(+/+) and Nrf2(-/-) mice by STZ injection. Sulforaphane (SF) or cinnamic aldehyde (CA) was administered 2 weeks after STZ injection and metabolic indices and renal structure and function were assessed (18 weeks). Markers of diabetes including blood glucose, insulin, polydipsia, polyuria, and weight loss were measured. Pathological alterations and oxidative damage in glomeruli were also determined. Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed. The molecular mechanisms of Nrf2-mediated protection were investigated in an in vitro model using human renal mesangial cells (HRMCs).

Results: SF or CA significantly attenuated common metabolic disorder symptoms associated with diabetes in Nrf2(+/+) but not in Nrf2(-/-) mice, indicating SF and CA function through specific activation of the Nrf2 pathway. Furthermore, SF or CA improved renal performance and minimized pathological alterations in the glomerulus of STZ-Nrf2(+/+) mice. Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs. In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

Conclusions: We provide experimental evidence indicating that dietary compounds targeting Nrf2 activation can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / administration & dosage
  • Acrolein / analogs & derivatives*
  • Acrolein / pharmacology
  • Acrolein / therapeutic use
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / physiopathology
  • Diabetic Nephropathies / prevention & control*
  • Dose-Response Relationship, Drug
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Isothiocyanates
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney / physiopathology
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / agonists*
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects
  • RNA Interference
  • RNA, Small Interfering
  • Random Allocation
  • Reactive Oxygen Species / metabolism
  • Sulfoxides
  • Thiocyanates / administration & dosage
  • Thiocyanates / pharmacology
  • Thiocyanates / therapeutic use*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Extracellular Matrix Proteins
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sulfoxides
  • Thiocyanates
  • Transforming Growth Factor beta1
  • Acrolein
  • sulforaphane
  • cinnamaldehyde