Whole-Body but Not Hepatic Knockdown of Chemerin by Antisense Oligonucleotide Decreases Blood Pressure in Rats

Abstract

Chemerin is an inflammatory adipokine positively associated with hypertension and obesity. The majority of chemerin derives from the liver and adipose tissue, however, their individual contributions to blood pressure are unknown. We began studying chemerin in the normal rat using antisense oligonucleotides (ASO) with whole-body activity (Gen 2.5 chemerin ASO) or liver-restricted activity (GalNAc chemerin ASO). We hypothesized that in normotensive male Sprague-Dawley rats, circulating chemerin is predominately liver-derived and regulates blood pressure. A dosing study of the Gen 2.5 chemerin ASO (with a scrambled control ASO) supported 25 mg/kg as the appropriate dose. GalNAc chemerin ASO was also assessed and used at 10 mg/kg. Radiotelemetry monitored mean arterial pressure (MAP) for a 1-week baseline and weekly subcutaneous ASO injections for 4 weeks. Two days after the final injection, animals were euthanized for tissue reverse transcription-polymerase chain reaction and chemerin Western analysis. Gen 2.5 chemerin ASO treatments reduced chemerin mRNA and protein in liver, retroperitoneal fat (RP), and mesenteric perivascular adipose tissue (mPVAT), as well as reducing protein in plasma. GalNAc chemerin ASO treatments reduced chemerin mRNA and protein in liver and chemerin protein in plasma but had no effect on expression in RP fat or mPVAT. Gen 2.5 chemerin ASO treatment reduced MAP compared with control ASO but was unchanged in animals receiving the GalNAc chemerin ASO. Although circulating chemerin is liver-derived, it does not play a major role in blood pressure regulation. Local effects of chemerin from fat may explain this discrepancy and support chemerin's association with hypertension and obesity.

Chemerin Isoforms and Activity in Obesity

“…In female rats, chemerin deficiency was associated with lower pressures, as one would have expected [ 78 ]. A second study using male rats observed decreased arterial blood pressure upon chemerin knock-down [ 79 ]. These studies show that chemerin has a causative function in blood pressure control, which is modified by gender.…”

Chemerin as a Driver of Hypertension: A Consideration

“…In normal male Sprague-Dawley rats, chemerin ASO treatment reduced mean arterial blood pressure by ~7 mm Hg. 116 These data, combined with others discussed below, have been redrawn from 116 , 117 in Figure 6. Similarly, the GalNAc ASO (liver-specific) against chemerin abolished liver chemerin mRNA, chemerin protein and reduced circulating chemerin levels to near zero, as determined by Western analysis.…”

“…Similarly, the GalNAc ASO (liver-specific) against chemerin abolished liver chemerin mRNA, chemerin protein and reduced circulating chemerin levels to near zero, as determined by Western analysis. 116 However, this same ASO was unable to reduce blood pressure . This suggests that while hepatic contributions dominate circulating plasma chemerin, liver chemerin is not involved in blood pressure determination.…”

Parental Dietary Protein Source and the Role of CMKLR1 in Determining the Severity of Dahl Salt-Sensitive Hypertension

“…CMKLR1 was the only gene found to be significantly differentially expressed in each of the comparisons made between SS/casein and SS/gluten, as well as between 0.4% and 4.0% NaCl. CMKLR1 (chemokine like receptor 1) is one of the three receptors associated with the prohypertensive and proinflammatory adipokine, chemerin 17 , and the benefits of either CMKLR1 inhibition or chemerin neutralization as potential therapeutics is a new and exciting area of research [18][19][20][21] . Utilizing a commercially available ELISA (LifeSpan BioSciences, Inc.), chemerin levels were measured in the serum, urine, and renal tissue (cortex and outer medulla) of Dahl SS rats fed either 0.4% or 4.0% NaCl for 3 weeks ( Figure S2).…”