Is There a Sweet Spot for Nrf2 Activation in the Treatment of Diabetic Kidney Disease?

  1. Vivek Bhalla
  1. Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, CA
  1. Corresponding author: Vivek Bhalla, vbhalla{at}

Diabetes-associated chronic kidney disease (CKD) continues to be a major contributor to morbidity and mortality in the U.S. and the world. Diabetic kidney disease is the most common reason that Americans are started on renal replacement therapy (1), and as the incidence of diabetes continues to increase, the health and economic consequences of nephropathy and other complications will rise in parallel (2). Unfortunately, there are no known treatments to reverse or arrest progression of diabetic kidney disease. Current treatment guidelines recently published by the National Kidney Foundation demonstrate the paucity of targeted therapies (3). The main recommendations include treatment of hyperglycemia, hypertension, and dyslipidemia, and use of inhibitors of the renin-angiotensin system if the patient has significant albuminuria. Thus, there is significant interest in identifying new therapeutic targets to prevent both development and progression of diabetic kidney disease.

Oxidative stress and inflammation have been implicated as contributors to the progression of CKD from a variety of causes, including diabetes. Recently, a particularly active area of investigation has focused on modulation of the transcription factor Nrf2 (nuclear factor erythroid 2−related factor 2). Nrf2 induces protective, so-called phase 2 antioxidant genes by interacting with cis-acting response elements in their respective promoters (4). This transcription factor is degraded by a ubiquitin ligase complex, which includes Keap1 (Kelch-like ECH-associated protein 1). A series …

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