Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice.

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^FA/FA mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1^FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process

SUBMITTER: Rush BM 

PROVIDER: S-EPMC7785672 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature