Editors' ChoiceDiabetes

NRF2 much of a good thing

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaar4435
DOI: 10.1126/scitranslmed.aar4435


Chronic hyperglycemia induces hypertension and renal injury through nuclear factor erythroid 2–related factor 2 (NRF2)–stimulation of the renin-angiotensin system.

Nuclear factor erythroid 2–related factor 2 (NRF2) is a key regulator of the cellular antioxidant response. Phenolic antioxidants have long been known to protect against chemical carcinogens, typically by activating the NRF2 pathway. Numerous clinical trials of NRF2 activators are under way for treatment of disorders ranging from cancer to schizophrenia. One NRF2 activator, dimethyl fumarate, is approved for treatment of multiple sclerosis. Prolonged activation of NRF2, however, causes tissue damage: In clinical trials for type 2 diabetes, NRF2 activators initially showed promise for renal protection, but studies of longer duration were discontinued early due to increased mortality, hypertension, and albuminuria. There may be a role for NRF2 inhibitors in clinical medicine.

To better understand the role of NRF2 in the development of hypertension and nephropathy in diabetes, Zhao et al. investigated the relationship between NRF2 and renin-angiotensin system (RAS) gene expression in the mouse kidney. Hyperglycemia increased NRF2 expression in murine renal proximal tubule cells, activating RAS with increased angiotensinogen and angiotensin-converting enzyme expression and decreased angiotensin-converting enzyme-2 and angiotensin 1-7 receptor expression. As expected, activation of RAS resulted in hypertension in diabetic mice. Deletion of Nrf2 reversed the RAS gene expression pattern, lowered blood pressure, and attenuated the development of tubulointerstitial fibrosis in diabetic mice.

Transfection of rat renal proximal tubule cells with Nrf2 small interfering RNA (siRNA) reduced nuclear NRF2 expression only in the setting of hyperglycemia. Nrf2 siRNA also prevented activation of the RAS at the mRNA level. Pretreatment with the NRF2 inhibitor trigonelline prevented hyperglycemia-stimulated RAS mRNA expression. This effect of trigonelline was abolished by the NRF2 activator oltipraz. In the diabetic mouse model, treatment with trigonelline decreased blood pressure, attenuated renal damage, and decreased RAS activation gene expression. These effects were also reversed by oltipraz. In summary, NRF2 activation by oxidative stress from hyperglycemia stimulates intrarenal RAS gene expression, contributing to the development of hypertension and nephropathy. Modulating this pathway could be important for the prevention of diabetes complications.

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