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Nephrol Dial Transplant. 2018 May 1;33(5):771-783. doi: 10.1093/ndt/gfx299.

Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction.

Author information

1
Department of Nephrology, The First Hospital of China Medical University, Shenyang, China.
2
Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, China.
3
Department of Medical Biochemistry, Tohoku University of Medicine, Sendai, Japan.

Abstract

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, α-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 α-SMA protein levels were increased. Nrf2 deletion decreased expression of antioxidative genes (Gclc and Ho-1) and increased expression of inflammatory response genes (Tgfβ, Tnf, IL-6, IL-1β 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 response while decreasing antioxidative responses. The renal protective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by antioxidative and anti-inflammatory pathways.

PMID:
29126308
DOI:
10.1093/ndt/gfx299

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