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Chronic continuous hypoxia decreases the expression of SLC4A7 (NBCn1) and SLC4A10 (NCBE) in mouse brain
Li-Ming Chen1, Inyeong Choi, Gabriel G Haddad
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA. liming.chen@case.edu
Abstract:
In the mammalian CNS, hypoxia causes a wide range of physiological effects, and these effects often depend on the stage of development. Among the effects are alterations in pH homeostasis. Na+-coupled HCO3(-) transporters can play critical roles in intracellular pH regulation and several, such as NCBE and NBCn1, are expressed abundantly in the central nervous system. In the present study, we examined the effect of chronic continuous hypoxia on the expression of two electroneutral Na-coupled HCO3(-) transporters, SLC4a7 (NBCn1) and SLC4a10 (NCBE), in mouse brain, the first such study on any acid-base transporter. We placed the mice in normobaric chambers and either maintained normoxia (21% inspired O2) or imposed continuous chronic hypoxia (11% O2) for a duration of either 14 days or 28 days, starting from ages of either postnatal age 2 days (P2) or P90. We assessed protein abundance by Western blot analysis, loading equal amounts of total protein for each condition. In most cases, hypoxia reduced NBCn1 levels by 20-50%, and NCBE levels by 15-40% in cerebral cortex, subcortex, cerebellum, and hippocampus, both after 14 and 28 days, and in both pups and adults. We hypothesize that these decreases, which are out of proportion to the expected overall decreases in brain protein levels, may especially be important for reducing energy consumption.
Insights
Hypoxia significantly decreases the expression of two key pH regulators, NBCn1 and NCBE, in the developing and adult mouse brain. These changes in acid-base transporters may help reduce brain energy consumption during low oxygen conditions.
Area of Science:
- Neuroscience
- Physiology
- Biochemistry
Background:
- Hypoxia impacts mammalian central nervous system (CNS) physiology, with effects varying by developmental stage.
- Intracellular pH regulation is crucial, and Na+-coupled HCO3- transporters like NBCn1 and NCBE play significant roles in the CNS.
- Acid-base balance is vital for neuronal function, especially under stress conditions like hypoxia.
Purpose of the Study:
- To investigate the effect of chronic continuous hypoxia on the expression of two electroneutral Na-coupled HCO3- transporters, SLC4a7 (NBCn1) and SLC4a10 (NCBE), in the mouse brain.
- To determine if hypoxia alters the protein levels of NBCn1 and NCBE in different brain regions and at various developmental stages.
- To explore the potential role of these transporters in energy metabolism under hypoxic conditions.
Main Methods:
- Mice were exposed to normoxia or chronic continuous hypoxia (11% O2) for 14 or 28 days.
- Hypoxia exposure began at either postnatal day 2 (P2) or postnatal day 90 (P90) to assess developmental effects.
- Protein abundance of NBCn1 and NCBE was quantified using Western blot analysis in various brain regions (cerebral cortex, subcortex, cerebellum, hippocampus).
Main Results:
- Chronic hypoxia significantly reduced NBCn1 protein levels by 20-50% across multiple brain regions.
- Hypoxia also decreased NCBE protein levels by 15-40% in the examined brain areas.
- These reductions were observed in both developing (P2) and adult (P90) mice after both 14 and 28 days of hypoxia.
Conclusions:
- Chronic hypoxia downregulates the expression of NBCn1 and NCBE in the mouse brain, irrespective of age.
- The observed decreases in these acid-base transporters are likely a mechanism to conserve energy during prolonged low oxygen exposure.
- This study provides the first evidence of hypoxia-induced changes in brain acid-base transporters, highlighting their potential role in neuroprotection and energy homeostasis.
