Impaired expression of HIF-2α induces compensatory expression of HIF-1α for the recovery from anemia

Abstract

Erythropoiesis is strongly influenced by the interactions between stromal cells and erythroid progenitors, as well as by a key regulatory factor, erythropoietin (EPO). We previously generated mice with a knockdown mutation of Hif-2α (referred to as kd/kd) and found that these kd/kd mice exhibited normocytic anemia, even though the EPO expression was not severely affected. However, the VCAM-1 expression in spleen endothelial cells (EC), which is regulated by HIF-2α, was impaired, resulting in defective erythroid maturation. A deficiency of HIF-2α clearly led to pancytopenia. However, the critical level of HIF-2α required for erythropoiesis has not yet been elucidated. In this study, we generated HIF-2α knockdown/knockout heterozygous mice (kd/null). Strikingly, anemia was observed in the kd/null mice, but the red blood cell indices were significantly improved compared to those of kd/kd mice. In the spleens of kd/null mice, higher HIF-1α activity and expansion of the red pulp area were observed compared to those of kd/kd mice. Importantly, EC isolated from kd/null spleens showed high expression of VEGF receptors, FLK-1 and FLT-1, which are regulated by HIF-1α instead of HIF-2α under hypoxic conditions. We also found higher expression of phosphorylated ERK and higher proliferative activity in the EC isolated from kd/null mice compared to those from kd/kd mice. While the HIF-2α expression was diminished, HIF-1α bound to the HRE region in the promoters of genes that are normally regulated by HIF-2α. These results suggest that there is a compensatory pathway involving HIF-1α that regulates the expression of some HIF-2α target genes.

Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia

“…Increased hemolysis may be caused by dysfunction of RBCs correlated with (I) defects of Hb (hemoglobinopathies) (18, 94, 161, 199), including alterations in structure and function of Hb chains; (II) defects of cytoskeletal proteins such as spectrin and ankyrin, which are essential for maintaining cell shape and integrity (19, 134, 149, 169); (III) defects in metabolic enzymes catalyzing the pentose phosphate cycle (126, 147) such as deficiency of G6PDH; (IV) redox dysregulation and defects of antioxidant enzymes (63, 84); (V) presence of antibodies directed against surface antigens on RBCs, such as antibodies anti-A, or anti-B blood group antigens (formed as a consequence of transfusion of allogenic blood from the wrong blood group), or autoimmune antibodies resulting in enhanced damage of RBC membranes (14, 92, 124, 160, 164, 178); (VI) chronic inflammation, disorders of cytokine production, and chronic diseases (97, 105, 154); (VII) side effects of drug/poisoning (32); (VIII) other genetic defects (155, 187); or (IX) RBC extrinsic factors (102, 108, 113, 142, 180). Another important cause of anemia is the loss of RBCs due to acute or chronic bleeding (59).…”

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

“…Importantly, although endogenous HIF-2 alone was shown to be inefficient in compensating for HIF-1 function during hypoxia [ 46 ], it has been also reported that in the absence of HIF-1, the exogenous HIF-2 was able to activate HIF-1-specific genes and vice versa [ 46 , 47 ]. Furthermore, in HIF-2α knockdown mice, HIF-1α regulates the expression of genes that are normally regulated by HIF-2α [ 48 ].…”

Astrocyte HIF-2α supports learning in a passive avoidance paradigm under hypoxic stress

“…The expression pattern of HIF-1α, HIF-2α, and related gene targets within neurons and astrocytes may be co-dependent, with HIF and HIF-controlled target proteins synthesized in cells exerting a paracrine function 109 upon the other. Indeed, compensatory roles for both HIF-1α and HIF-2α have been described, 110 , 111 raising the question of how neurons are compensating by activating their own HIF-response system and if this is also affected by aging. Additionally, the balance of HIF-1α vs HIF-2α expression may shift when one or the other is diminished; however, we did not identify this in primary astrocytes in culture.…”