Key result
Germline knockout of CD14 exacerbated salt-sensitive hypertension and renal injury in female animals but not males, an effect that was completely abrogated by ovariectomy.
Why the study?
CD14 is associated with cardiovascular and hypertensive disease and upregulated in renal macrophages of Dahl salt-sensitive animals, but whether it contributes to elevated blood pressure and renal injury remained unknown.
Does CD14 knockout alter blood pressure and renal injury in Dahl salt-sensitive rats on a high-salt diet?
Does CD14 knockout alter blood pressure and renal injury in Dahl salt-sensitive rats on a high-salt diet?
CD14 knockout exacerbates salt-sensitive hypertension and renal injury in female but not male Dahl salt-sensitive rats, revealing a sex-specific role of CD14 in immune activation and hypertensive disease.
Answers are grounded in this paper and cite their sources.
CD14 effects on salt-sensitive hypertension appear sex-specific in animals; leaves open targeted immune modulation for human disease.
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.
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Fehrenbach et al. (2020) studied Salt-sensitive hypertension and renal injury. CD14 knockout vs. Wild-type (CD14 +/+) was evaluated on Blood pressure and renal injury. Germline knockout of CD14 exacerbated salt-sensitive hypertension and renal injury in female animals but not males, an effect that was completely abrogated by ovariectomy.
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