Exclusion of Angiotensin I-Converting Enzyme as a Candidate Gene Involved In Exudative Inflammatory Resistance in F344/N Rats

Jafarian-Tehrani, Mehrnaz; Listwak, Samuel J.; Barrientos, Ruth M.; Michaud, Annie; Corvol, Pierre; Sternberg, Esther M.

doi:10.1007/bf03401940

Cited by 7 publications

(5 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reciprocal nature of tissue Ace and Ac-SDKP levels in susceptible tissues of Fischer and Lewis strains may explain the moderation of end organ damage in the latter strain. Using the N-terminally specific tetrapeptide substrate, both Ace activity and catalytic properties have been reported to be identical in both Lewis and Fischer strains (48). …”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage

Liu

Bellamy

Bailey

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.

show abstract

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage

Liu

Bellamy

Bailey

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Sequencing of the coding regions of these genes in the parental strains used in this intercross indicated no difference between LEW/N and F344/N rats in the CRHR1, and a point mutation in ACE resulting in a leucine to phenylalanine switch near the N-terminal active site of the enzyme (Jafarian-Tehrani et al 2000). Further analysis revealed that while the non-specific activity of ACE was elevated in the strain that showed the mutation (F344/N rats), there was no difference between the two strains in specific activity of the enzyme, and treatment of the rats with ACE inhibitors did not affect the inflammatory phenotype.…”

Section: Genetics Of Autoimmune/inflammatory Disease Susceptibilitymentioning

confidence: 94%

Neuroendocrine regulation of autoimmune/inflammatory disease

Sternberg¹

2001

Journal of Endocrinology

277

162

View full text Add to dashboard Cite

Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; locally, at sites of inflammation. Estrogens also play an important role in immune modulation, and contribute to the approximately 2-to 10-fold higher incidence of autoimmune/inflammatory diseases seen in females of all mammalian species. During inflammation, cytokines from the periphery activate the central nervous system through multiple routes. This results in stimulation of the hypothalamic-pituitary-adrenal axis which, in turn through the immunosuppressive effects of the glucocorticoids, generally inhibits inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1-to a TH2-type pattern. Interruptions of this loop at any level and through multiple mechanisms, whether genetic, or through surgical or pharmacological interventions, can render an inflammatory resistant host susceptible to inflammatory disease. Over-activation of this axis, as occurs during stress, can also affect severity of infectious disease through the immunosuppressive effects of the glucocorticoids. These interactions have been clearly demonstrated in many animal models, across species, strains and diseases, and are also relevant to human inflammatory, autoimmune and allergic illnesses, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, allergic asthma and atopic skin disease. While many genes and environmental factors contribute to susceptibility and resistance to autoimmune/ inflammatory diseases, a full understanding of the molecular effects on immune responses of combinations of neuropeptides, neurohormones and neurotransmitters at all levels has opened up new therapeutic approaches and are essential for the design of future therapies based on such principles.

show abstract

“…There is good evidence in the mammalian circulation that HA is metabolically stable. The tripeptides hippuryl-L-histidyl-L-leucine (van Platerink et al, 2007) and hippurylglycylglycine (Jafarian-Tehrani et al, 2000) are commonly employed as substrates for angiotensin converting enzyme (ACE; peptidyl-dipeptidase A; EC 3.4.15.1) and are hydrolyzed by dipeptidase activity leaving the stable HA. Circulating HAwill certainly be exposed to ACE since it is expressed mainly in lung, vascular endothelium and kidney (Femia et al, 2008).…”

Section: The Glycine Deportation Systemmentioning

confidence: 99%