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- Title
The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.
- Authors
Liu, Manchang; Reddy, Narsa M; Higbee, Elizabeth M; Potteti, Haranatha R; Noel, Sanjeev; Racusen, Lorraine; Kensler, Thomas W; Sporn, Michael B; Reddy, Sekhar P; Rabb, Hamid
- Abstract
Acute kidney injury (AKI) caused by ischemia-reperfusion is a major clinical problem in both native and transplanted kidneys. We had previously shown that deficiency of Nrf2, a potent bZIP transcription factor that binds to the antioxidant response element, enhances susceptibility to experimental ischemic AKI. Here we further explored the role of Nrf2 in AKI by amplifying Nrf2 activation in vivo and in vitro with the synthetic triterpenoid CDDO-imidazolide. Mice treated with CDDO-imidazolide and undergoing experimental bilateral ischemic AKI had improved survival and renal function. Treated mice had improved renal histology with a decrease in tubular injury, as well as a decrease in proinflammatory cytokine and chemokine production compared with vehicle-treated mice. In an exploration of protective mechanisms, we found an upregulation of Nrf2 target antioxidant genes in CDDO-imidazolide-treated mouse kidneys. Furthermore, Nrf2-deficient mice treated with CDDO-imidazolide had no significant improvement in mortality, renal function or histology, proinflammatory cytokine gene expression, and no significant increase in antioxidant gene expression. In vitro studies demonstrated that the renal epithelial cells were likely an important target of CDDO-imidazolide. Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition.
- Subjects
TRITERPENOIDS; REPERFUSION injury; MICE as carriers of disease; KIDNEY transplantation; GENE expression; EPITHELIAL cells
- Publication
Kidney International, 2014, Vol 85, Issue 1, p134
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.2013.357