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Published on: June 7, 2014
Effects of hypoxia-reoxygenation stimuli on renal redox status and nuclear factor erythroid 2-related factor 2
Camille Faes1,2, Gaëtan Juban3, Emeline Aufradet1
1Interuniversity Laboratory of Human Movement Biology EA7424, Univ Lyon - University Claude Bernard Lyon 1, Villeurbanne, France.
New Findings:
What is the central question of this study? What are the effects of repeated subclinical vaso-occlusions on nuclear factor erythroid 2 related factor 2 (Nrf2) and oxidative stress balance regulation in the kidney of transgenic SAD mice? What is the main finding and its importance? In response to hypoxia-reoxygenation, nuclear Nrf2 protein expression decreased in the kidney of SAD mice while haem oxygenase transcripts were increased. This suggest that in SAD mice, other transcription factors than Nrf2 could be involved in renal antioxidant gene regulation in response to hypoxia-reoxygenation.
Abstract:
Hypoxia-reoxygenation (H/R) stress is known to increase oxidative stress in transgenic sickle mice and can cause organ failure. Here we described the effects of H/R on nuclear factor erythroid 2-related factor 2 (Nrf2) as a putative regulator of redox status in the kidneys of SAD mice investigating Nrf2-regulated antioxidant enzymes. Transgenic SAD mice and healthy C57Bl/6J mice were exposed to 4 h of hypoxia followed by various times of reoxygenation at ambient air (2 or 6 h). Regardless of the conditions (i.e. normoxia or H/R), SAD mice expressed higher renal oxidative stress levels. Nuclear Nrf2 protein expression decreased after 2 h post-hypoxia only in the medulla region of the kidney and only in SAD mice. Simultaneously, haem oxygenase transcripts were affected by H/R stimulus with a significant enhancement after 2 h post-hypoxia. Similarly, hypoxia inducible factor-1α staining increased after 2 h post-hypoxia in SAD mice in both cortex and medulla areas. Our data confirm that the kidneys are organs that are particularly sensitive to H/R stimuli in sickle cell SAD mice. Also, these results suggest an effect of the duration of recovery period (short vs. long) and specific responses according to kidney areas, medulla vs. cortex, on Nrf2 expression in response to H/R stimuli in SAD mice.
Insights
In sickle cell mice, hypoxia-reoxygenation stress impacts kidney function. Nuclear factor erythroid 2-related factor 2 (Nrf2) expression decreased, suggesting other factors regulate antioxidant genes in the kidneys.
Area of Science:
- Nephrology
- Hematology
- Molecular Biology
Background:
- Sickle cell disease (SCD) involves oxidative stress and potential organ damage, particularly in the kidneys.
- Hypoxia-reoxygenation (H/R) is a known stressor that exacerbates oxidative stress in SCD models.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular antioxidant responses.
Purpose of the Study:
- To investigate the effects of H/R stress on Nrf2 and oxidative stress balance in the kidneys of transgenic sickle cell disease (SAD) mice.
- To explore the regulation of renal antioxidant enzymes in response to H/R in SAD mice.
Main Methods:
- Transgenic SAD mice and healthy C57Bl/6J mice were subjected to 4 hours of hypoxia followed by 2 or 6 hours of reoxygenation.
- Kidney tissues were analyzed for oxidative stress levels, Nrf2 protein expression, haem oxygenase transcripts, and hypoxia-inducible factor-1α (HIF-1α) staining.
Main Results:
- SAD mice exhibited higher renal oxidative stress levels compared to controls, irrespective of normoxia or H/R conditions.
- Nuclear Nrf2 protein expression decreased in the kidney medulla of SAD mice after 2 hours of reoxygenation following hypoxia.
- Haem oxygenase transcripts and HIF-1α staining increased in SAD mice kidneys post-hypoxia, indicating an H/R response.
- Kidney regions (medulla vs. cortex) and recovery duration influenced Nrf2 expression patterns.
Conclusions:
- The kidneys are highly sensitive to H/R stimuli in SAD mice.
- The observed decrease in Nrf2 expression suggests that other transcription factors may be involved in regulating renal antioxidant genes during H/R in SAD mice.
- These findings highlight the complex redox regulation in the kidneys of sickle cell mouse models under stress.
