Journal
ANTIOXIDANTS
Volume 12, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/antiox12071440
Keywords
aging; NRF2; ischemic reperfusion injury; recovery from acute kidney injury
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This study investigated the role of NRF2 in restoring kidney function after IRI in the aging kidney. The expression of NRF2 decreased significantly in the kidneys of old mice, and renal recovery after IRI was impaired in these mice. In NRF2 knockout mice, renal injury during the recovery phase after IRI was aggravated. These findings suggest that NRF2 may be a therapeutic target for the aging kidney.
Deteriorating kidney function is frequently observed in the elderly population, as well as vulnerability to acute kidney failure, such as ischemic/reperfusion injury (IRI), and inadequate recovery from IRI is one of the mechanisms of kidney dysfunction in the elderly. The potential mediators in the progression of kidney dysfunction in the aging kidney have not yet been clearly revealed. In this study, we investigated the role of nuclear factor erythroid 2-related factor 2 (NRF2), which is an essential regulator of cellular redox homeostasis, in restoring kidney function after IRI in the aging kidney. NRF2 expression decreased significantly in the kidneys of old mice, as well as histologic and functional renal recovery after IRI; 45-min renal pedicle clamping was retarded in old compared with young mice. Persistent renal injury during the recovery phase after IRI was aggravated in NRF2 knockout (KO) mice compared to wild-type mice. Oxidative stress occurred in NRF2 KO old mice during the IRI recovery phase along with decreased expression of mitochondrial OXPHOS-related proteins and a reduction in mitochondrial ATP content. In vitro, hypoxia/reoxygenation (H/R) injury was aggravated in senescent human proximal tubuloepithelial cells after NRF2 restriction using NRF2 siRNA, which also increased the level of oxidative stress and deteriorated mitochondrial dysfunction. Treating the mice with an NRF2 activator, CDDO-Me, alleviated the injury. These results suggest that NRF2 may be a therapeutic target for the aging kidney.
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