Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice.
Details
Serval ID
serval:BIB_EE6812558D88
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice.
Journal
Kidney international
ISSN
1523-1755 (Electronic)
ISSN-L
0085-2538
Publication state
Published
Issued date
01/2021
Peer-reviewed
Oui
Volume
99
Number
1
Pages
102-116
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1). These Keap1 <sup>FA/FA</sup> mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1 <sup>FA/FA</sup> mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1 <sup>FA/FA</sup> mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.
Keywords
Animals, Humans, Kelch-Like ECH-Associated Protein 1/genetics, Kelch-Like ECH-Associated Protein 1/metabolism, Mice, Mice, Knockout, NF-E2-Related Factor 2/genetics, NF-E2-Related Factor 2/metabolism, Proteinuria/genetics, Renal Insufficiency, Chronic/genetics, Keap1, albuminuria, bardoxolone methyl, circadian rhythm, glomerulosclerosis, nephrin
Pubmed
Web of science
Create date
03/09/2023 20:25
Last modification date
23/09/2023 6:55