Evolutionary Adaptation of Aquaporin-4 in Yak () Brain to High-Altitude Hypoxia of Qinghai-Tibetan Plateau.

In high-altitude animals, brain cell resilience against hypoxia stress is one critical evolutionary step that has promoted individual survival and species adaptation to the environment. Aquaporin-4 (AQP4) is implicated in a number of physiopathological processes, particularly in the development of brain edema, and other functions such as the regulation of extracellular space volume, potassium buffering, waste clearance, and calcium signaling. Still, the role of AQP4 in the adaptation to high-altitude hypoxia remains unknown. The yak () is the only large mammal that is currently known to have adapted to the high-altitude hypoxic environment of the Qinghai-Tibet Plateau (>4000 m above sea level). In this study, we cloned the complementary DNA (cDNA) for yak and analyzed structural differences of AQP4 between yak and cattle. We used reverse transcription quantitative polymerase chain reaction and western blot to investigate whether the expression of AQP4 mRNA and protein was different in brain of yak and cattle. In addition, immunohistochemistry was use to analyze the localization and expression of AQP4 in brain of yak and cattle. Immunohistochemical results have shown that AQP4 is expressed in many regions of the yak brain, and both protein and messenger RNA (mRNA) levels are significantly lower than those of low-altitude cattle (). Phylogenetic analysis revealed that yak AQP4 is evolutionarily conserved. Interestingly, a substitution of Ala (cattle) to Ser in position 82, and eight additional amino acid residues composing an α-helix region are present in yak AQP4 protein. These sequence modifications potentially modulate the function of AQP4 in distinct environments. Our findings suggest that AQP4 may have an important role in the resistance to cerebral edema through low expression and maintenance of normal physiological function in the yak brain.