Hypoxia and erythropoietin in the regulation of aquaporins

Abstract

Aquaporins (AQPs) constitute a family of small transmembrane proteins that facilitate osmotically-driven water transport, and in some cases that of small solutes. Several roles for AQPs have been identified, such as the regulation of brain and corneal water balance, neural signal transduction and angiogenesis. Moreover, various members of this family have been found in high-grade tumors of different tissue origins. Although recent investigations have shed light on the structure and function of AQPs, many aspects of their regulation remain to be explored. Accumulating evidence places hypoxia as a modulator of AQP expression in different tissues, and some members of this family have been shown to contain hypoxia-responsive sequence elements in their promoters. However, there is still little knowledge about the signaling pathways relaying information on O2 homeostasis to the aquaporin gene. The maintenance of adequate O2 levels is essential to support cellular function. Hypoxia results from an imbalance between the supply of O2 to the tissues and its consumption, which may be the outcome of pathological conditions such as obstructive apnea, anemia, ischemia and atherosclerosis. Through the upregulation of the hypoxia-inducible transcription factor, cells undergoing chronic hypoxic stress can modulate the expression levels of genes related to metabolism, cell proliferation, differentiation and apoptotic cell death. Hypoxia can also drive tumor growth and vascularization, thus compromising the efficacy of treatments. Erythropoietin is the paradigm of hypoxia-inducible gene expression, as it drives the increase of erythrocyte mass in response to low O2 levels. However, the finding of erythropoietin receptors in various cell types shows its biological relevance goes beyond the erythroid compartment. Erythropoietin is regarded as a proangiogenic factor, as well as a tissue protectant from hypoxic/ischemic injuries. Although there is scarce experimental evidence supporting the modulation of AQPs by erythropoietin, some of these water channels have been shown to participate in the biological effects of the growth factor, such as AQP1 in endothelial cell migration and AQP4 in the prevention of edema and ischemic damage in the rat brain.This Chapter will emphasize the evidence of AQP modulation by hypoxia and erythropoietin, as these water channels are increasingly valued as potential biomarkers of disease, as well as pharmacological targets for the treatment of brain and renal injuries, cardiovascular disorders and cancer.