Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1942-1952. https://doi.org/10.1172/JCI24354.
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Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog

Abstract

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release–inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga–/– and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga–/– mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga–/– mice. Loss of the physiological “brake” catestatin in Chga–/– mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.

Authors

Nitish R. Mahapatra, Daniel T. O’Connor, Sucheta M. Vaingankar, Amiya P. Sinha Hikim, Manjula Mahata, Saugata Ray, Eugenie Staite, Hongjiang Wu, Yusu Gu, Nancy Dalton, Brian P. Kennedy, Michael G. Ziegler, John Ross Jr., Sushil K. Mahata

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Figure 1

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Chga gene targeting. (A) Chga wild-type gene structure. Chga from the ...
Chga gene targeting. (A) Chga wild-type gene structure. Chga from the isogenic mouse 129/SvJ strain showing the positions of wild-type Chga’s 8 coding exons, as well as restriction sites and the locations of the 3 Chga segments (arms) used to construct the targeting vector. Also shown is an undisrupted, wild-type ˜13-kbp diagnostic BamHI (asterisk) fragment, spanning the promoter, exons 13, and corresponding introns. (B) Structure of the homologously targeted Chga gene. A Southern blot probe (˜1.3 kb BamHI/XhoI fragment) detected a ˜7.3 kbp BamHI (asterisks) fragment after homologous recombination. (C) Southern blot results. While the probe (B; ˜1.3 kbp BamHI/XhoI fragment) detected only a ˜13 kbp fragment in wild-type DNA (A), it detected both ˜13-kbp (wild-type) and ˜7.3-kbp (targeted) BamHI fragments in ES cell genomic DNA after homologous recombination disrupted 1 Chga allele. Lane 1: 1-kbp extension ladder; lane 2: wild-type ES cells (13-kbp band only); lane 3: clone B7 ES cells with homologous recombination in 1 Chga allele; lane 4: clone C5 cells with homologous recombination in 1 Chga allele. (D) Chga gene after homologous integration of the targeting construct into mouse genomic DNA (Chga locus on mouse chromosome 12), followed by Cre-loxP–mediated recombination (type I deletion, between the first and third loxP sites; dashed line). The triangles represent loxP recognition sites. Asterisks indicate BamHI sites flanking the diagnostic 7.3-kbp BamHI fragment.