Kelch-like ECT2-interacting protein KLEIP regulates late-stage pulmonary maturation via Hif-2α in mice.
Respiratory distress syndrome (RDS) caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late-stage embryonic lung development is driven by hypoxia and the hypoxia-inducible transcription factors Hif-1α and Hif-2α, which act as important regulators for lung development. Expression of the BTB-and kelch-domain-containing (BTB-kelch) protein KLEIP (Kelch-like ECT2-interacting protein; also named Klhl20) is controlled by two hypoxia response elements, and KLEIP regulates stabilization and transcriptional activation of Hif-2α. Based on the available data, we hypothesized an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP(-/-) mice. Here, we show that about half of the KLEIP(-/-) neonates die due to respiratory failure that is caused by insufficient aeration, reduced septal thinning, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in embryonic day (E) 18.5 lungs identified KLEIP in lung capillaries, and showed strongly reduced mRNA and protein levels for Hif-2α and VEGF; such reduced levels are associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP(-/-) neonates, normalized lung maturation, vascularization, aeration and function, and increased neonatal Hif-2α expression. Thus, the experimental study shows that respiratory failure in KLEIP(-/-) neonates is determined by insufficient angiocrine Hif-2α-VEGF signaling and that betamethasone activates this newly identified signaling cascade in late-stage embryonic lung development.
Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Nicole
N
Woik
Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
Christian T
CT
Dietz
Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Kathrin
K
Schäker
Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany. jens.kroll@medma.uni-heidelberg.de.
Jens
J
Kroll
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D005938:Glucocorticoids / Q000627:therapeutic use; D008168:Lung / Q000254:growth & development*; D008171:Lung Diseases / Q000188:drug therapy; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D012131:Respiratory Insufficiency; D015996:Survival Rate; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D005938:Glucocorticoids; D008840:Microfilament Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
BTB-kelch protein KLEIP; Betamethasone; Endothelial cells; Hif-2α; Respiratory distress syndrome