Astrocyte‐specific deletion of Kir4.1 increases normoxic ventilation after acclimatization to chronic sustained hypoxia.

Abstract

Chronic sustained hypoxia (CH) produces ventilatory acclimatization to hypoxia (VAH), which involves time‐dependent increases of ventilation in normoxia and the hypoxic ventilatory response (HVR). Previous results show that glia are activated by CH and contribute to VAH but the contribution of astrocytes involved in central CO2‐sensitivity to VAH is not known. We tested the hypothesis that inwardly rectifying K+ 4.1 channels in astrocytes contribute to VAH using conditional gene deletion in transgenic mice. Conditional knockout (cKO) Kir4.1 mice had loxP sites at both ends of the entire Kir4.1 open reading frame and WT mice did not. WT and cKO Kir4.1 mice expressed tdTomato reporter and Cre‐recombinase/ERT2 receptors in astrocytes under the control of hGFAP promoter. Immunofluorescence against markers of astrocytes and Kir4.1 confirmed that tamoxifen treatment decreased Kir4.1 expression in astrocytes in CO2‐senstivie areas of the medulla of cKO Kir4.1 but not WT mice. After CH (PiO2 = 70 mmHg for 1 week), ventilation measured with barometric pressure plethysmography increased in normoxia, acute hypoxia and acute hypercapnia relative to chronically normoxic control mice. Ventilation was greater in normoxia after CH in Kir4.1cKO than in WT because of greater respiratory frequency and tidal volume. Ventilation in acute hypoxia or hypercapnia after CH was not significantly different between genotypes and metabolic rate was similar between genotypes at all O2 levels. The results support a role in astrocytes in the persistent hyperventilation in normoxia with VAH.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.