The Nrf2 pathway in the progression of renal disease
Carlamaria Zoja, Ariela Benigni, Giuseppe Remuzzi
Istituto di Ricerche Farmacologiche "Mario Negri"
The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.
SUPPL. 1
https://doi.org/10.1093/ndt/gft224
bardoxolone
Keap1
10.1093/ndt/gft224
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methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate Medicine & Life Sciences 100%
Disease Progression Medicine & Life Sciences 44%
Phase II Clinical Trials Medicine & Life Sciences 17%
NF-kappa B Medicine & Life Sciences 14%
Diabetic Nephropathies Medicine & Life Sciences 14%
Genetic Promoter Regions Medicine & Life Sciences 13%
Zoja, C., Benigni, A., & Remuzzi, G. (2014). The Nrf2 pathway in the progression of renal disease. Nephrology Dialysis Transplantation, 29(SUPPL. 1). https://doi.org/10.1093/ndt/gft224
The Nrf2 pathway in the progression of renal disease. / Zoja, Carlamaria; Benigni, Ariela; Remuzzi, Giuseppe.
In: Nephrology Dialysis Transplantation, Vol. 29, No. SUPPL. 1, 2014.
Zoja, C, Benigni, A & Remuzzi, G 2014, 'The Nrf2 pathway in the progression of renal disease', Nephrology Dialysis Transplantation, vol. 29, no. SUPPL. 1. https://doi.org/10.1093/ndt/gft224
Zoja C, Benigni A, Remuzzi G. The Nrf2 pathway in the progression of renal disease. Nephrology Dialysis Transplantation. 2014;29(SUPPL. 1). https://doi.org/10.1093/ndt/gft224
Zoja, Carlamaria ; Benigni, Ariela ; Remuzzi, Giuseppe. / The Nrf2 pathway in the progression of renal disease. In: Nephrology Dialysis Transplantation. 2014 ; Vol. 29, No. SUPPL. 1.
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title = "The Nrf2 pathway in the progression of renal disease",
abstract = "The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.",
keywords = "bardoxolone, diabetic nephropathy, Keap1",
author = "Carlamaria Zoja and Ariela Benigni and Giuseppe Remuzzi",
doi = "10.1093/ndt/gft224",
journal = "Nephrology Dialysis Transplantation",
number = "SUPPL. 1",
T1 - The Nrf2 pathway in the progression of renal disease
AU - Zoja, Carlamaria
AU - Benigni, Ariela
AU - Remuzzi, Giuseppe
N2 - The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.
AB - The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.
KW - bardoxolone
KW - diabetic nephropathy
KW - Keap1
U2 - 10.1093/ndt/gft224
DO - 10.1093/ndt/gft224
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - SUPPL. 1