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. 2022 Dec 13:13:1014366.
doi: 10.3389/fendo.2022.1014366. eCollection 2022.

Clinical identification of expressed proteins in adrenal medullary hyperplasia detected with hypertension

He Ma  1 , Ke Wang  2 , Bingjie Lai  3 , Xueyan Zhang  4 , Yang Lv  1 , Ranwei Li  5
Affiliations

Clinical identification of expressed proteins in adrenal medullary hyperplasia detected with hypertension

He Ma et al. Front Endocrinol (Lausanne). .

Abstract

Background: Hypertension remains a challenging public health problem worldwide, and adrenal gland-related diseases are one class of the major causes for secondary hypertension. Among them, one relatively rare pattern is adrenal hyperplastic hypertension caused by adrenal medullary hyperplasia (AMH), leading to excessive secretion of autonomic catecholamine. Given that the pathological changes of adrenal medulla are not well correlated to the onset and even severity of secondary hypertension, the molecular basis why some AMH patients are accompanied with hypertension remains unclear and is worth exploring.

Aims: For this reason, this study aims at investigating differentially expressed proteins in clinical AMH tissue, with special focus on the potential contribution of these differentially expressed proteins to AMH development, in order to have a better understanding of mechanisms how AMH leads to secondary hypertension to some extent.

Methods and results: To this end, AMH specimens were successfully obtained and verified through computed tomography (CT) and haematoxylin-eosin (HE) staining. Proteomic analyses of AMH and control tissues revealed 782 kinds of differentially expressed proteins. Compared with the control tissue, there were 357 types of upregulated proteins and 425 types of downregulated proteins detected in AMH tissue. Of interest, these differentially expressed proteins were significantly enriched in 60 gene ontology terms (P < 0.05), including 28 biological process terms, 14 molecular function terms, and 18 cellular component terms. Pathway analysis further indicated that 306 proteins exert their functions in at least one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Western blotting showed enhanced expression of phenylethanolamine N- methyltransferase (PNMT), myelin protein zero (MPZ), and Ras-related protein Rab-3C (RAB3C), and reduced expression of cluster of differentiation 36 (CD36) observed in AMH tissue in comparison with controls.

Conclusions: Clinical AMH specimens display a different proteomic profile compared to control tissue. Of note, PNMT, MPZ, RAB3C, and CD36 are found to differentially expressed and can be potential targets for AMH, providing a theoretical basis for mechanistic exploration of AMH along with hypertension.

Keywords: CD36; MPZ; PNMT; RAB3C; adrenal medullary hyperplasia; hypertension; proteomics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Clinical diagnosis and pathological verification of AMH. (A, B) Representative computed tomography (CT) scan images of control adrenal tissue (A) and AMH tissue (B). (C, D) Representative haematoxylin-eosin (HE) staining images of control adrenal tissue (C) and AMH tissue (D).
Figure 2
Figure 2
Gene Ontology (GO) analysis results of differentially expressed proteins in AMH tissues compared with adjacent control tissues. Analyses were performed using three terms: biological process (BP), molecular function (MF), and cellular component (CC).
Figure 3
Figure 3
GO enrichment analysis results. The top 30 enriched GO terms of target proteins were displayed in comparison with background proteins. Difference set: target proteins; Reference set: background proteins.
Figure 4
Figure 4
KEGG pathway functional analysis results. Major pathways include tyrosine 3-monooxygenase (EC:1.14.16.2), dopamine beta-monooxygenase (EC:1.14.17.1), phenylethanolamine N-methyltransferase (EC:2.1.1.28), tyrosine 3-monooxygenase (EC:1.14.16.2), aromatic-L-amino-acid/L-tryptophan decarboxylase (EC:4.1.1.28/4.1.1.105), maleylacetoacetate isomerase (EC:5.2.1.2), maleylacetoacetate isomerase (EC:5.2.1.2), and primary-amine oxidase (EC:1.4.3.21).
Figure 5
Figure 5
KEGG pathway enrichment analysis results. The top 30 enriched pathways of target proteins were displayed in comparison with background proteins. Difference set: target proteins; Reference set: background proteins.
Figure 6
Figure 6
Protein-protein interaction (PPI) network based on differentially expressed proteins. Each node indicates an individual protein, red nodes indicate upregulated proteins in AMH tissue, and green nodes indicate downregulated proteins in AMH tissue. (A) PPI network based on upregulated MPZ.P0. (B) PPI network based on upregulated RAB3C. (C) PPI network based on upregulated PNMT. (D) PPI network based on downregulated CD36.
Figure 7
Figure 7
Representative Western blots and quantification results of four kinds of differentially expressed proteins. (A) These four proteins displayed distinctly different expression in AMH and control tissues. MPZ.P0, RAB3C, and PNMT were increased in AMH, whereas CD36 was decreased in AMH in comparison with controls. n = 4 for each group. β-Actin was used as the loading control. (B) Quantification results of MPZ.P0 normalized to β-Actin. (C) Quantification results of RAB3C normalized to β-Actin. (D) Quantification results of PNMT normalized to β-Actin. (E) Quantification results of CD36 normalized to β-Actin. * P < 0.05, ** P < 0.01.
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