Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling
Receptors for advanced glycation end products (RAGE) are multiligand cell surface receptors found most abundantly in lung tissue. This study sought to evaluate the role of RAGE in lung development by using a transgenic (TG) mouse model that spatially and temporally controlled RAGE overexpression. Hi...
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2024-12-01
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| author | Derek M. Clarke Madison N. Kirkham Logan B. Beck Carrleigh Campbell Hayden Alcorn Benjamin T. Bikman Juan A. Arroyo Paul R. Reynolds |
| author_facet | Derek M. Clarke Madison N. Kirkham Logan B. Beck Carrleigh Campbell Hayden Alcorn Benjamin T. Bikman Juan A. Arroyo Paul R. Reynolds |
| author_sort | Derek M. Clarke |
| collection | DOAJ |
| description | Receptors for advanced glycation end products (RAGE) are multiligand cell surface receptors found most abundantly in lung tissue. This study sought to evaluate the role of RAGE in lung development by using a transgenic (TG) mouse model that spatially and temporally controlled RAGE overexpression. Histological imaging revealed that RAGE upregulation from embryonic day (E) 15.5 to E18.5 led to a thickened alveolar parenchyma and reduced alveolar surface area, while RAGE overexpression from E0 to E18.5 caused a significant loss of tissue and decreased architecture. Mitochondrial dysfunction was a hallmark of RAGE-mediated disruption, with decreased levels of anti-apoptotic BCL-W and elevated pro-apoptotic BID, SMAC, and HTRA2, indicating compromised mitochondrial integrity and increased intrinsic apoptotic activity. Extrinsic apoptotic signaling was similarly dysregulated, as evidenced by the increased expression of TNFRSF21, Fas/FasL, and Trail R2 in E0-18.5 RAGE TG mice. Additionally, reductions in IGFBP-3 and IGFBP-4, coupled with elevated p53 and decreased p27 expression, highlighted disruptions in the cell survival and cycle regulatory pathways. Despite the compensatory upregulation of inhibitors of apoptosis proteins (cIAP-2, XIAP, and Survivin), tissue loss and structural damage persisted. These findings underscore RAGE’s role as a pivotal modulator of lung development. Specifically, the timing of RAGE upregulation significantly impacts lung development by influencing pathways that cause distinct histological phenotypes. This research may foreshadow how RAGE signaling plausibly contributes to developmental lung diseases. |
| format | Article |
| id | doaj-art-e4fd78c526444980879100bbd4daf75d |
| institution | DOAJ |
| issn | 1467-3037 1467-3045 |
| language | English |
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| spelling | doaj-art-e4fd78c526444980879100bbd4daf75d2025-08-20T02:53:19ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452024-12-014612144531446310.3390/cimb46120867Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic SignalingDerek M. Clarke0Madison N. Kirkham1Logan B. Beck2Carrleigh Campbell3Hayden Alcorn4Benjamin T. Bikman5Juan A. Arroyo6Paul R. Reynolds7Department of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USADepartment of Cell Biology and Physiology, Brigham Young University, 3054 Life Sciences Building, Provo, UT 84602, USAReceptors for advanced glycation end products (RAGE) are multiligand cell surface receptors found most abundantly in lung tissue. This study sought to evaluate the role of RAGE in lung development by using a transgenic (TG) mouse model that spatially and temporally controlled RAGE overexpression. Histological imaging revealed that RAGE upregulation from embryonic day (E) 15.5 to E18.5 led to a thickened alveolar parenchyma and reduced alveolar surface area, while RAGE overexpression from E0 to E18.5 caused a significant loss of tissue and decreased architecture. Mitochondrial dysfunction was a hallmark of RAGE-mediated disruption, with decreased levels of anti-apoptotic BCL-W and elevated pro-apoptotic BID, SMAC, and HTRA2, indicating compromised mitochondrial integrity and increased intrinsic apoptotic activity. Extrinsic apoptotic signaling was similarly dysregulated, as evidenced by the increased expression of TNFRSF21, Fas/FasL, and Trail R2 in E0-18.5 RAGE TG mice. Additionally, reductions in IGFBP-3 and IGFBP-4, coupled with elevated p53 and decreased p27 expression, highlighted disruptions in the cell survival and cycle regulatory pathways. Despite the compensatory upregulation of inhibitors of apoptosis proteins (cIAP-2, XIAP, and Survivin), tissue loss and structural damage persisted. These findings underscore RAGE’s role as a pivotal modulator of lung development. Specifically, the timing of RAGE upregulation significantly impacts lung development by influencing pathways that cause distinct histological phenotypes. This research may foreshadow how RAGE signaling plausibly contributes to developmental lung diseases.https://www.mdpi.com/1467-3045/46/12/867RAGElungembryotransgenicapoptosis |
| spellingShingle | Derek M. Clarke Madison N. Kirkham Logan B. Beck Carrleigh Campbell Hayden Alcorn Benjamin T. Bikman Juan A. Arroyo Paul R. Reynolds Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling Current Issues in Molecular Biology RAGE lung embryo transgenic apoptosis |
| title | Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling |
| title_full | Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling |
| title_fullStr | Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling |
| title_full_unstemmed | Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling |
| title_short | Temporal RAGE Over-Expression Disrupts Lung Development by Modulating Apoptotic Signaling |
| title_sort | temporal rage over expression disrupts lung development by modulating apoptotic signaling |
| topic | RAGE lung embryo transgenic apoptosis |
| url | https://www.mdpi.com/1467-3045/46/12/867 |
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