TY - JOUR
T1 - Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction
AU - Kong, Weiwei
AU - Fu, Jingqi
AU - Liu, Nan
AU - Jiao, Congcong
AU - Guo, Guangying
AU - Luan, Junjun
AU - Wang, Huihui
AU - Yao, Li
AU - Wang, Lining
AU - Yamamoto, Masayuki
AU - Pi, Jingbo
AU - Zhou, Hua
N1 - Funding Information:
This research was supported by the Chinese Nature Science Foundation (81370835 to H.Z., 81573106 to J.P. and 81402635 to J.F.), Pandeng Scholar of Liaoning Province (2013222 to H.Z. and J.P.) and Startup Funding of China Medical University (to J.P.).
Publisher Copyright:
© The Author 2017.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Background. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central mediator of cellular responses to oxidative stress. We hypothesized that Nrf2 modulates progression from acute tubular damage to renal fibrosis. We asked whether Nrf2 deletion increases renal injury in mice following unilateral ureteral obstruction (UUO). Methods.We explored the time course of renal injury and Nrf2 expression in Nrf2/ mice following UUO. We compared Nrf2/ and Nrf2/ mice following UUO in tubular damage, transdifferentiation [vimentin, proliferating cell nuclear antigen (PCNA)], fibrosis [fibronectin, a-smooth muscle actin (SMA)], antioxidative and inflammatory responses. We studied Nrf2 in renal biopsies of patients with acute, subacute and chronic tubulointerstitial nephritis (TIN). Results. In Nrf2/ mice, renal Nrf2 expression and Nrf2- regulated glutamate-cysteine ligase catalytic (Gclc) and heme oxygenase-1 (Ho-1) were elevated, and renal injury occurred between 2 and 14 days after UUO. On Day 2 following UUO, in Nrf2/ mice compared with Nrf2/ mice, tubular damage, apoptotic cell numbers, cleaved caspase3 and cleaved-poly ADP-ribose polymerase were increased. On Day 5, protein levels of vimentin and PCNA and the co-expressed cells of both proteins were increased. On Day 14, fibronectin and a-SMA protein levels were increased. Nrf2 deletion decreased expression of antioxidative genes (Gclc and Ho-1) and increased expression of inflammatory response genes (Tgfb, Tnf, IL-6, IL-1b and F4/80). Finally, Nrf2 expression was upregulated in renal biopsies of patients with TIN. Conclusions. Following UUO, Nrf2 deficiency increased tubular damage, transdifferentiation, fibrosis and inflammatory esponse while decreasing antioxidative responses. The renal protective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by antioxidative and antiinflammatory pathways.
AB - Background. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central mediator of cellular responses to oxidative stress. We hypothesized that Nrf2 modulates progression from acute tubular damage to renal fibrosis. We asked whether Nrf2 deletion increases renal injury in mice following unilateral ureteral obstruction (UUO). Methods.We explored the time course of renal injury and Nrf2 expression in Nrf2/ mice following UUO. We compared Nrf2/ and Nrf2/ mice following UUO in tubular damage, transdifferentiation [vimentin, proliferating cell nuclear antigen (PCNA)], fibrosis [fibronectin, a-smooth muscle actin (SMA)], antioxidative and inflammatory responses. We studied Nrf2 in renal biopsies of patients with acute, subacute and chronic tubulointerstitial nephritis (TIN). Results. In Nrf2/ mice, renal Nrf2 expression and Nrf2- regulated glutamate-cysteine ligase catalytic (Gclc) and heme oxygenase-1 (Ho-1) were elevated, and renal injury occurred between 2 and 14 days after UUO. On Day 2 following UUO, in Nrf2/ mice compared with Nrf2/ mice, tubular damage, apoptotic cell numbers, cleaved caspase3 and cleaved-poly ADP-ribose polymerase were increased. On Day 5, protein levels of vimentin and PCNA and the co-expressed cells of both proteins were increased. On Day 14, fibronectin and a-SMA protein levels were increased. Nrf2 deletion decreased expression of antioxidative genes (Gclc and Ho-1) and increased expression of inflammatory response genes (Tgfb, Tnf, IL-6, IL-1b and F4/80). Finally, Nrf2 expression was upregulated in renal biopsies of patients with TIN. Conclusions. Following UUO, Nrf2 deficiency increased tubular damage, transdifferentiation, fibrosis and inflammatory esponse while decreasing antioxidative responses. The renal protective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by antioxidative and antiinflammatory pathways.
KW - apoptosis
KW - Nrf2
KW - transdifferentiation
KW - tubulointerstitial fibrosis
KW - UUO
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U2 - 10.1093/ndt/gfx299
DO - 10.1093/ndt/gfx299
M3 - Article
C2 - 29126308
AN - SCOPUS:85047333620
SN - 0931-0509
VL - 33
SP - 771
EP - 783
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 5
ER -