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Development of the hypersecretory phenotype in the population of adrenal chromaffin cells from prehypertensive SHRs

  • Molecular and cellular mechanisms of disease
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Abstract

The hypersecretory phenotype of adrenal chromaffin cells (CCs) from early spontaneously hypertensive rats (SHRs) mainly results from enhanced Ca2+-induced Ca2+-release (CICR). A key question is if these abnormalities can be traced to the prehypertensive stage. Spontaneous and stimulus-induced catecholamine exocytosis, intracellular Ca2+ signals, and dense-core granule size and density were examined in CCs from prehypertensive and hypertensive SHRs and compared with age-matched Wistar-Kyoto rats (WKY). During the prehypertensive stage, the depolarization-elicited catecholamine exocytosis was ~ 2.9-fold greater in SHR than in WKY CCs. Interestingly, in half of CCs the exocytosis was indistinguishable from WKY CCs, while it was between 3- and sixfold larger in the other half. Likewise, caffeine-induced exocytosis was ~ twofold larger in prehypertensive SHR. Accordingly, depolarization and caffeine application elicited [Ca2+]i rises ~ 1.5-fold larger in prehypertensive SHR than in WKY CCs. Ryanodine reduced the depolarization-induced secretion in prehypertensive SHR by 57%, compared to 14% in WKY CCs, suggesting a greater contribution of intracellular Ca2+ release to exocytosis. In SHR CCs, the mean spike amplitude and charge per spike were significantly larger than in WKY CCs, regardless of age and stimulus type. This difference in granule content could explain in part the enhanced exocytosis in SHR CCs. However, electron microscopy did not reveal significant differences in granule size between SHRs and WKY rats’ adrenal medulla. Nonetheless, preSHR and hypSHR display 63% and 82% more granules than WKY, which could explain in part the enhanced catecholamine secretion. The mechanism responsible for the heterogeneous population of prehypertensive SHR CCs and the bias towards secreting more medium and large granules remains unexplained.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors wish to thank Drs. Citlali Trueta and Fredy Cifuentes for discussions and advice, MVZ Claudia V. Rivera-Cerecedo for expert animal breeding, and Francisco Perez for expert computing assistance. Peña del Castillo J. G. is a Ph. D. student from the Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and received the fellowship #306030 from CONACyT. This study was conducted as part of the requirements to obtain her Ph. D. Supported by Grants 315803 and 314839 to A-HC from Consejo Nacional de Ciencia y Tecnología (CONACYT), México and PAPIIT AG200119 from Dirección General de Asuntos del Personal Académico (DGAPA-UNAM). Also supported by a grant from Ministerio de Ciencia e Innovación (Project PID2020-114824GB-I00 to LMG).

Funding

This study is financially supported by Grants 315803 (Laboratorio Nacional de Canalopatías) from Consejo Nacional de Ciencia y Tecnología (CONACYT), México, and PAPIIT AG200119 from Dirección General de Asuntos del Personal Académico (DGAPA-UNAM) and by a grant of Ministerio de Ciencia e Innovación (Project PID2020-114824GB-I00 to LMG).

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Authors and Affiliations

  1. Departamento Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, México

    Johanna Guadalupe Peña del Castillo, Diana Millán-Aldaco & Arturo Hernández-Cruz

  2. Cátedras CONACyT, Instituto Nacional de Psiquiatría Ramón de La Fuente Muñiz, Laboratorio de Fisiología Celular, Calzada México Xochimilco No. 101, Ciudad de México, 14370, México

    Pedro Segura-Chama

  3. Unidad de Imagenología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, 04510, México

    Ruth Rincón-Heredia

  4. Instituto de Neurociencias, Centro Mixto Universidad Miguel Hernández-CSIC, 03550, Sant Joan d’Alacant, Alicante, Spain

    Yolanda Giménez-Molina, José Villanueva & Luis Miguel Gutiérrez

  5. Laboratorio Nacional de Canalopatías, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, 04510, México

    Arturo Hernández-Cruz

Authors
  1. Johanna Guadalupe Peña del Castillo
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  2. Pedro Segura-Chama
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  3. Ruth Rincón-Heredia
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  4. Diana Millán-Aldaco
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  6. José Villanueva
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  7. Luis Miguel Gutiérrez
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  8. Arturo Hernández-Cruz
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Contributions

Peña-del Castillo performed the experiments, analyzed data, prepared figures, and wrote the paper, Segura Chama performed research and analyzed data, Rincón-Heredia analyzed data, Diana Millán-Aldaco performed research, contributed new methods, Yolanda Giménez-Molina, José Villanueva, and Luis Miguel Gutiérrez, contributed new method and analyzed data. Arturo Hernández-Cruz conceived the study, wrote the paper.

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Correspondence to Arturo Hernández-Cruz.

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Research involving animals complies with the Mexican Guide’s guidelines for the Care and Use of Laboratory Animals of the Secretary of Agriculture (SAGARPA NOM-062-Z00–1999). The Institutional Committee of Care and Use of Laboratory Animals (CICUAL-IFC) approved the experimental protocols used here (protocol AHC24-141). Research does not involve human patients.

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Peña del Castillo, J.G., Segura-Chama, P., Rincón-Heredia, R. et al. Development of the hypersecretory phenotype in the population of adrenal chromaffin cells from prehypertensive SHRs. Pflugers Arch - Eur J Physiol 473, 1775–1793 (2021). https://doi.org/10.1007/s00424-021-02614-2

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