Chemerin as a Driver of Hypertension: A Consideration

Abstract

The protein chemerin (tazarotene-induced gene, TIG2; RARRES2) is a relatively new adipokine. Many studies support that circulating chemerin levels associate strongly and positively with body mass index, visceral fat, and blood pressure. Here, we focus on the specific relationship of chemerin and blood pressure with the goal of understanding whether and how chemerin drives (pathological) changes in blood pressure such that it could be interfered with therapeutically. We dissect the biosynthesis of chemerin and how current antihypertensive medications change chemerin metabolism. This is followed with a review of what is known about where chemerin is synthesized in the body and what chemerin and its receptors can do to the physiological function of organs important to blood pressure determination (e.g., brain, heart, kidneys, blood vessels, adrenal, and sympathetic nervous system). We synthesize from the literature our best understanding of the mechanisms by which chemerin modifies blood pressure, with knowledge that plasma/serum levels of chemerin may be limited in their pathological relevance. This review reveals several gaps in our knowledge of chemerin biology that could be filled by the collective work of protein chemists, biologists, pharmacologists, and clinicians.

Keywords: blood pressure; chemerin; hypertension; obesity.

Figure 1.

Expression of chemerin mRNA in human and rat organs. For both species, the liver was set to 1 given that the absolute magnitude of chemerin mRNA is greatest in the liver of both species. The human levels are reported from the Human Atlas (https://www.proteinatlas.org/ENSG00000106538-RARRES2/tissue) where mRNA is a conglomerate of that expressed in a Consensus, HPA and GTEx dataset. The rat measures, less in number because of the size of the study, were done in the laboratory of one of the authors, Dr Adam Mullick and were measured relative to RiboGreen expression. Where a measure is absent in the rat study, the bar is marked with not yet measured (NYM) or a reference is placed for a different study that validates the expression of mRNA in that specific tissue.

Figure 2.

Chemerin secretion, processing and functioning at membrane bound receptors (Chemerin1 and Chemerin2) and chaperone receptor CCRL2. Abbreviations: aa, amino acid; Erk, ERK MAPK; p38, p38 MAPK; RARRES2, retinoic acid receptor responder 2, the chemerin gene.

Figure 3.

Experimental tools to investigate the chemerin/chemerin receptor axis. Abbreviations: ELISA, enzyme linked immunosorbent assay; KO, knockout; RT-PCR, reverse transcriptase-polymerase chain reaction. Red capped lines = inhibition. Green arrow = stimulation.

Figure 4.

The physiological actions of chemerin in primary organs of the CV system. ? = insufficient basic research.

Figure 5.

Compilation of reported (superscripted numbers) chemerin concentration (plasma or serum) in human, from 0 to 400 µg/l. Abbreviations: HTN, hypertensive; Met, metabolic; NT, normotensive; PCOS, polycystic ovarian syndrome; T2DM, type 2 diabetes mellitus.

Figure 6.

Effect of ASOs on mean arterial blood pressure (MAP) and plasma chemerin protein expression in the male Sprague-Dawley (left) and high salt (HS) or high fat (HF) Dahl S male rat. Whole-body ASO knocked down chemerin in all tissues, while the liver-specific ASO knocked down chemerin largely in the liver. Dahl S rats were either on a control, high fat (60% fat), or high salt (4% salt) diet. Data are adapted from refs. ^,. Bars represent means ± SEM for number of animals indicated by N. Abbreviation: ASO, antisense oligonucleotide.

Figure 7.

Working hypothesis of the local actions of chemerin in the vasculature as facilitated by the perivascular adipose tissue (PVAT) as a source of chemerin that could activate chemerin1 receptors on the sympathetic nerve (yellow) or smooth muscle cell to stimulate vascular contraction.