Sexual Dimorphic Role of CD14 (Cluster of Differentiation 14) in Salt-Sensitive Hypertension and Renal Injury. Hypertension 2021 Jan;77(1):228-240
Date
12/01/2020Pubmed ID
33249861Pubmed Central ID
PMC9732708DOI
10.1161/HYPERTENSIONAHA.120.14928Scopus ID
2-s2.0-85097815793 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
Genomic sequence and gene expression association studies in animals and humans have identified genes that may be integral in the pathogenesis of various diseases. CD14 (cluster of differentiation 14)-a cell surface protein involved in innate immune system activation-is one such gene associated with cardiovascular and hypertensive disease. We previously showed that this gene is upregulated in renal macrophages of Dahl salt-sensitive animals fed a high-salt diet; here we test the hypothesis that CD14 contributes to the elevated pressure and renal injury observed in salt-sensitive hypertension. Using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), we created a targeted mutation in the CD14 gene on the Dahl SS (SS/JrHSDMcwi) background and validated the absence of CD14 peptides via mass spectrometry. Radiotelemetry was used to monitor blood pressure in wild-type and CD14-/- animals challenged with high salt and identified infiltrating renal immune cells via flow cytometry. Germline knockout of CD14 exacerbated salt-sensitive hypertension and renal injury in female animals but not males. CD14-/- females demonstrated increased infiltrating macrophages but no difference in infiltrating lymphocytes. Transplant of CD14+/+ or CD14-/- bone marrow was used to isolate the effects of CD14 knockout to hematopoietic cells and confirmed that the differential phenotype observed was due to knockout of CD14 in hematopoietic cells. Ovariectomy was used to remove the influence of female sex hormones, which completely abrogated the effect of CD14 knockout. These studies provide a novel treatment target and evidence of a new dichotomy in immune activation between sexes within the context of hypertensive disease where CD14 regulates immune cell activation and renal injury.
Author List
Fehrenbach DJ, Abais-Battad JM, Dasinger JH, Lund H, Keppel T, Zemaj J, Cherian-Shaw M, Gundry RL, Geurts AM, Dwinell MR, Mattson DLAuthors
Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acute Kidney InjuryAnimals
Estradiol
Female
Hypertension
Kidney
Lipopolysaccharide Receptors
Male
Rats
Rats, Inbred Dahl
Sex Characteristics
