Angiotensin II plays an essential role in the maintenance of blood pressure and blood volume. It is a peptide hormone that causes vasoconstriction,a sensation of thirst,and stimulation of the adrenal cortex and aldosterone.
Derived from the cleavage of angiotensin I by the angiotensin converting enzyme,angiotensin II is involved in the renin-angiotensin system (RAS).
Angiotensin II is the subject of much scientific research and is already the target of many anti-hypertensive drugs (ACE inhibitors,ARBs or AT1 receptor antagonists).
Involvement in Covid-19
The Sars-CoV-2 responsible for Covid-19 binds to angiotensin II converting enzyme receptors to infect human cells. These receptors are found in large numbers in certain organs,so the virus can have deleterious effects:
– in the nose,these receptors are numerous on the mucous membrane,resulting in the loss of the sense of smell;
– In the brain,these receptors are present in the cortex and brain stem and affected patients suffer from convulsions,confusion and inflammation of the brain;
– The virus would also enter via these receptors into the heart and the cells lining the blood vessels. This causes arrhythmia and clotting,which can lead to pulmonary embolism or stroke.
Involvement in Alzheimer’s disease
Studies have shown that patients treated with ARBs were less likely to get the disease. And their condition was less severe if they did get it.
Stable isotope labeled Angiotensin II for quantitative proteomics
Angiotensin II is involved in many pathologies and can be measured in patients by selected reaction monitoring. Methods for the absolute quantification of angiotensin II are described in the scientific articles below.
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Angiotensin II acts as a peptide hormone and component of renin-angiotensin- system (RAS) regulating the blood pressure,and seems to be involved in renal and vascular disorders. There is no reliable quantification method for angiotensin II available until now and the angiotensin II plasma levels described in the literature are correspondingly strongly divergent. Therefore,we developed and validated a sensitive,selective and reliable LC-ESI-MS/MS method for absolute quantification of angiotensin II concentration in human plasma based on the AQUA strategy.
Methods:
Plasma samples were extracted using MAX Oasis cartridges and were subjected to a further immunoaffinity-purification using immobilized anti-angiotensin II antibodies in order to isolate endogenous angiotensin II. Stable isotope ((13)C- and (15) N-) labeled angiotensin II was used as an internal standard. The fractionated samples were analysed using LC-ESI-MS/MS.
Results:
The calibration curve was established in plasma in the concentration range 6-240 pM (r(2) > 0.999). The developed and validated method was successfully applied for quantification of endogenous angiotensin II in human plasma of healthy volunteers and chronic kidney disease (CKD-5D) patients. The mean plasma angiotensin II levels were found to be 18.4 ± 3.3 pM in healthy subjects and 64.5 ± 32.4 pM in CKD-5D patients (each n =9).
Conclusion:
The LC-ESI-MS/MS-based method for quantification of angiotensin II levels in human plasma was successfully evaluated within the study. This method is applicable for clinical applications aiming at the validation of the impact of highly physiologically and pathophysiologically active angiotensin II.
2- Konvalinka A. et al. Clinical Proteomics (2016)
Angiotensin-II (Ang II) mediates progression of autosomal-dominant polycystic kidney disease (ADPKD) and other chronic kidney diseases (CKD). However,markers of kidney Ang II activity are lacking. We previously defined 83 Ang II-regulated proteins in vitro,which reflected kidney Ang II activity in vivo.
Methods
In this study,we developed selected reaction monitoring (SRM) assays for quantification of Ang II-regulated proteins in urine of ADPKD and CKD patients. We demonstrated that 47 of 83 Ang II-regulated transcripts were differentially expressed in cystic compared to normal kidney tissue. We then developed SRM assays for 18 Ang II-regulated proteins overexpressed in cysts and/or secreted in urine. Methods that yielded CV ≤ 6 % for control proteins,and recovery ~100 % were selected. Heavy-labeled peptides corresponding to 13 identified Ang II-regulated peptides were spiked into urine samples of 17 ADPKD patients,9 patients with CKD predicted to have high kidney Ang II activity and 11 healthy subjects. Samples were then digested and analyzed on triple-quadrupole mass spectrometer in duplicates.
Resluts
Calibration curves demonstrated linearity (R2 > 0.99) and within-run CVs < 9 % in the concentration range of 7/13 peptides. Peptide concentrations were normalized by urine creatinine. Deamidated peptide forms were monitored,and accounted for <15 % of the final concentrations. Urine excretion rates of proteins BST1,LAMB2,LYPA1,RHOB and TSP1 were significantly different (p < 0.05,one-way ANOVA) between patients with CKD,those with ADPKD and healthy controls. Urine protein excretion rates were highest in CKD patients and lowest in ADPKD patients. Univariate analysis demonstrated significant association between urine protein excretion rates of most proteins and disease group (p < 0.05,ANOVA) as well as sex (p < 0.05,unpaired t test). Multivariate analysis across protein concentration,age and sex demonstrated good separation between ADPKD and CKD patients.
Conclusions
We have optimized methods for quantification of Ang II-regulated proteins,and we demonstrated that they reflected differences in underlying kidney disease in this pilot study. High urine excretion of Ang II-regulated proteins in CKD patients likely reflects high kidney Ang II activity. Low excretion in ADPKD appears related to lack of communication between cysts and tubules. Future studies will determine whether urine excretion rate of Ang II-regulated proteins correlates with kidney Ang II activity in larger cohorts of chronic kidney disease patients.
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