In a database analysis, it would be difficult to determine whether the prescribed medications were actually taken, and therefore, the use of PDC may over- or underestimate actual medication adherence. As this retrospective cohort study was based on a claims database, there were inevitably other inherent limitations. For example, coding errors and typos are not uncommon in real-world practice.
In addition, blood pressure, an important measurement of the efficacy of antihypertensive agents, could not be obtained at the baseline period or during follow-up periods. Possible risk factors such as smoking and socioeconomic status, and their effects were also difficult to be well assessed in this study. Furthermore, the study group of the present analysis is limited to the Taiwanese population, which may not be representative of the Asian population or the world population.
A prospective randomized controlled trial is warranted for further validation of our results. In this retrospective database study in Taiwan, ARBs when compared with ACE inhibitors in FDC regimens that include CCBs were shown to be comparably effective at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients with no established cardiovascular diseases. The results remained the same for patients across all adherence statuses.
The authors thank all the subjects and staff involved in this study for their cooperation. They also thank Michael Wu's critical reading of the current paper. You may be trying to access this site from a secured browser on the server. Please enable scripts and reload this page.
Some error has occurred while processing your request. Please try after some time. Article as PDF 1. The authors have no conflicts of interest to disclose. Back to Top Article Outline. TABLE 1. A public health approach to global management of hypertension. Lancet ; — Cited Here PubMed CrossRef.
Clinical Relevance of Local Renin Angiotensin Systems
Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment.
JAMA ; — Mulrow CD, Pignone M. What are the elements of good treatment for hypertension? BMJ ; — Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. Trends in prevalence, awareness, management, and control of hypertension among United States adults, to J Am Coll Cardiol ; — Evidence for improved control of hypertension in Taiwan: — J Hypertens ; — Blood Press ; — Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension.
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How Can Local RAS be Shown to be Independent of the Circulating RAS?
This maneuver doubled Ang II concentrations. Injecting saline solution intraperitoneally into fresh-water-acclimated lampreys also decreased Ang II concentrations. The results suggest that Ang II may play a role in volume regulation of these primitive vertebrates. The data are consistent with the idea that the Ang II peptide has been around for million years. Missing from the authors' data are mass-spectrometry-determined amino acid sequences of the peptides. These results are fascinating; however, more precise methodologies would be important to prove beyond any doubt that the investigators indeed were dealing with Ang II [ 19 ].
To complement the available physiological evidence on the evolution of the RAAS, we used the information available from the gene and protein sequences in public databases [ 20 ]. Complete genomes are especially useful since they allow us to evaluate the presence of a given protein and also inform us of its absence. Particularly, the latter state-of-affairs can be very revealing [ 21 ]. We focused our analysis in the search for sequence homologs of genes encoding nine of the human proteins mentioned previously in 12 representative model organisms Fig. The genomes of these organisms, except the one of the elephant shark, Callorhinchus milii , have been completely sequenced.
Orthology was verified with reciprocal searches. Finally, the sequences collected were aligned, and construction of phylogenetic trees was used to verify that the sequences were orthologous to the human gene. We note that although the function of some proteins that we report has been experimentally verified, many are merely predicted translation products from genes resulting from genome sequencing projects awaiting verification.
Furthermore, sequencing of additional genomes could clearly make this analysis more complete. Phylogeny of the species whose sequences are studied in this review. The main groups displayed are the chordates, which comprise all species considered except Drosophila and Caenorhabditis , and display a notochord, at least at some point during their embryonic development.
Vertebrates are species displaying vertebra and comprise all considered chordate species, with the exception of Ciona and Amphioxus. Finally, the tetrapods comprise all our vertebrate species, with the exception of fishes, either cartilage fishes elephant shark, Callorhinchus Milii , bony fishes zebrafish, Danio rerio , coelacants, or lungfishes.
Homologs of nine human proteins of the renin—angiotensin—aldosterone system. Sequences are identified by GenPept identifiers. Empty cells are highlihgted in dark gray to remark that we did not find the corresponding ortholog in the indicated species. Cells shaded in light gray indicate genes that are ancestral to multiple human genes. The main pattern of our findings agrees with physiological evidence Fig. Most of the components emerge concomitantly to appearance of the juxtaglomerular apparatus.
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For instance, the zebrafish, Danio rerio , our representative of bony fishes, constitutes the taxon with the most primitive JGA [ 23 ] and already contains orthologs to eight of the nine proteins considered. The exception is the oncogene Mas, which seems to have evolved later in the tetrapod lineage. We found Mas in the frog Xenopus tropicalis , our amphibian representative. Orthologs of the nine genes could be found in all tetrapod species analyzed, indicating the molecular stability of the pathway.
We could not find the renin protein in Gallus gallus , the chicken, representing birds in our study. However, clear homology to full human renin was found in genomic shotgun sequences corresponding to chromosome 26 of Gallus gallus. These sequences have not been yet assembled to the current version of the Gallus gallus genome. Comparison of the RAAS in multiple species. Blanks indicate instances in which the property could not be found. Question marks denote instances of uncertain or contradictory data. Ciona intestinalis contains the two ACEs and the prorenin receptor, but the many components missing show evidence that these three proteins have functions ancestral to the RAAS.
After a large gap, our next closer relatives whose complete genomes we know, the bony fishes, have a human-like system, with two notable differences: a possible use of a precursor of aldosterone and the absence of the Mas receptor.
The tetrapods mammals, reptiles, amphibians, birds have the complete system, with the exception of renin, which could be missing in aves see main text. Angiotensinogen, because of its central role in the system, could be the best molecule to establish the time of RAAS emergence. We found an angiotensinogen ortholog in the shark Callorhinchus milii , confirming that the RAAS was established with the appearance of gnathostomata, the jawed fishes.
Unfortunately, the shark genome is not yet completely sequenced, and we could not find any other sequences of the genes we tested. We could not find an angiotensinogen ortholog in lampreys. We note that some lamprey sequences are currently annotated in GenBank as putative angiotensinogens e. Angiotensinogen displays a serpin domain Fig. Serpins are known as protease inhibitors [ 25 ]. Ancestral binding of angiotensinogen to proteases may have been a prerequisite to cleavage of angiotensinogen by proteases such as renin [ 26 ].
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Structural features of nine human proteins relevant to the RAAS. Red box on angiotensinogen diagram: Ang I sequence AG. Red symbols indicate protein cleavage sites. The fact that some of the genes analyzed existed prior to the appearance of angiotensinogen can be used to trace the ancestry of the system. However, the finding also indicates the incompleteness of our functional understanding regarding these genes. We observed P RR orthologs in all organisms with complete genomes analyzed, including Drosophila melanogaster , our insect representative, and the worm Caenorhabditis elegans.
The sequence length was fairly constant, suggesting a well-conserved domain organization. ATP6AP2 presumably gained function with respect to the binding of prorenin and renin, later in evolution [ 7 ]. Whether or not these two seemingly unrelated functions are interrelated remains to be determined [ 27 ]. We found orthologs of both proteins in Ciona intestinalis , the sea squirt, which is our tunicate representative and in Branchiostoma floridae , the amphioxus; both representing primitive chordates. These two model organisms lack most of the molecular and physiological components of the system, including angiotensinogen.
Both of these enzymes are active endopeptidases during fly development but seem to lack a clear function in adulthood [ 28 ]. This finding suggests that the enzymatic activity for the processing of angiotensinogen products existed prior to the appearance of angiotensinogen itself. Angiotensinogen could possibly have emerged as an adaptation to existing ACE metalloproteinases. It is interesting to note that ACE activity seems to be related to fertility and development in organisms ranging from insects to mouse.
ANCE has been suggested to play a role in the peptide-processing enzyme in seminal fluid of Drosophila [ 30 ]. In the mosquito Anopheles stephensi , ANCE may regulate embryogenesis when activated by blood meal [ 31 ], while in freshfly Neobellieria bullata , several substrates or inhibitors of ACE activity are present during development of ovaries, suggesting a role of ACE activity in the reproductive system [ 32 ]. Besides, an isoform of ACE is only present in germ cells of wild-type male mice [ 33 ], while male mice deficient for germinal ACE show infertility [ 34 ].
This state-of-affairs was proven for the Xanthomonas axonopodis pv. More significantly, our phylogenetic analysis clusters bacterial sequences with the ACE2 sequences of Ciona intestinalis and Branchiostoma floridae Fig. Our observation suggests that this bacterial family is the result of a horizontal transfer event involving an ancestral ACE2 that happened in an ancestor of Ciona intestinalis after the divergence of tunicates from other chordates. The structure of the bacterial phylogenetic tree suggests further events of horizontal transfer involving this gene between bacteria.
Besides their enzymatic properties, the ACEs have other non-catalytic functions [ 36 ]. Bacteria might exploit these other functions as well. Evolution of the ACE family. The numbers at the branches indicate number of bootstrapping tests that resulted in the marked grouping: Values close to the total used indicate reliable branches. The labels indicate the subfamily, a two letter abbreviation of the species name, GenPept identifier, and amino acid range.
Species abbreviations of eukaryotic species are dm Drosophila melanogaster , ci Ciona intestinalis , bf B. Multiple bacterial sequences including the X. This suggests that the bacterial sequences are a result of horizontal transfer from an ancestral chordate species. The ACE family originated before the divergence of chordates from arthropods. Gene duplications black dots have expanded this family, for example, leading to the existence of ACE1 and ACE2 in chordates. Multiple events of domain duplication red dots have happened in the ACE1 subfamily, an important one leading to the vertebrate ACE1, which contains an N-terminal and a C-terminal catalytic domain.
This sequence seems to have evolved into a pseudogene in humans blue line. Orthologs of vertebrate ACE2 are present in many bacterial species. Their close homology to non-vertebrate ACE2s suggests that they are the result of a single event of horizontal transfer from an ancestral non-vertebrate species. The grouping in the phylogenetic tree of the bacterial sequences analyzed here suggests that this initial event was followed by further events of horizontal transfer between bacterial species, indicating that bacterial ACEs have acquired a function that confers an evolutionary advantage to the species bearing it.
The alignment was examined, and phylogenetic trees were generated using ClustalX Version 2. In contrast, ACE orthologs have two such domains [ 37 ], Figs. The strong similarity between the N- and C-terminal domains in one Ciona intestinalis and in one Branchiostoma floridae sequence suggest that the proteins of the ACE subfamily have undergone multiple independent events of domain duplication like the one leading to the vertebrate ACEs.
In mice, the two domains have different importance in the development of hypertension, as has been shown by selective deletion of one of the two domains [ 38 ]. Finally, in mammals, we observed a further member of this family containing a single catalytic domain, termed ACE3. The function of ACE3 is unknown. The best characterized member is the mouse ACE3, which is expressed and produces a protein in sperm; however, gene deletion does not render mice infertile [ 39 ]. Orthologs of ACE3 exist in cow, dog, and rat, while the human counterpart is a pseudogene with multiple base deletions, insertions, and stop codons.
ACE3 expression could possibly regulate the expression of the parental ACE gene, a mechanism of post-transcriptional gene regulation that is known to exist for other pseudogenes [ 41 ]. We did not find orthologs of this gene outside of mammals. It is important to note that beside ACEs, other enzymes that can cleave Ang I to Ang II [ 5 ] have been found, such as chymase, a protein expressed in the mast cells of heart and blood vessels [ 5 ], and cathepsin G, a secreted serine peptidase of neutrophils and mast cells [ 42 ]. These proteins appear to have evolved well after the establishment of the RAAS.
We did not find any homologue in the most distant Ciona. This finding suggests that this protein family emerged after divergence of tunicates from primitive chordates. Again, the functional relationship of this gene with Ang II must have occurred later in evolution since angiotensinogen evolved later Fig. The Ang II receptor family may exhibit other ancestral functions. The MR probably predated angiotensinogen and renin. The gene for the ancient MR protein might have been duplicated in an ancestral organism before the emergence of bony fishes [ 43 , 44 ].
The primordial MR then evolved duplicated to become a glucocorticoid receptor GR. This interpretation suggests that volume regulation is older than stress-related responses. We traced MR easily to bony fishes. Our cartilage fish sequence left us with a question mark Fig. Ren-2 is mainly expressed in the salivary gland of males and is dramatically stimulated by aggression ,fold higher levels in saliva than plasma [ 46 ].
Possibly, the aspartyl protease serves to injure a bitten opponent or conceivably the protease serves a protective function for wound healing after a fight by wound licking. Interestingly, increasing angiotensinogen in the mouse by infusion increases blood pressure substantially. The normally fairly low levels of angiotensinogen in the blood of mice could be a response to the effectiveness of their salivary renin. The fact that Ren-2 is strain-specific suggests that the duplication of this gene is a relatively recent event. A relative paucity of renin substrate in the mouse could have favored this duplication [ 47 ].
Ren-2 actually provided the first successful transgenic-rat model of hypertension, underscoring its amazing effectiveness in cleaving rat cross species angiotensinogen [ 48 ]. The important finding of our study is that most of the RAAS component members began to appear with primitive chordates and tunicates. All of the important components were present with the development of bony fishes, with the exception of the Mas receptor, which appears in amphibians.
We found solid evidence that angiotensinogen made its appearance in cartilage fishes, but they are still a mystery as this is the only sequence of the RAAS available so far in sharks. This situation is unfortunate as this taxon is of crucial importance in the understanding of the evolution of volume regulation. We included the P RR in our analysis, although the protein has no known function in volume regulation. The receptor has a component that serves as an important adapter protein for a vacuolar ATPase, and for this reason, the sequence is probably much older than the RAAS-related function [ 7 ].
The function of this receptor is still not clear, so the time point when its interaction with prorenin and renin developed remains speculative.
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However, since studies on the renin-angiotensin system of birds, reptiles, amphibians and fishes are limited compared with those con- ducted in mammals, in some chapters descriptions are con- cerned primarily with mammals. It has taken a long time to write this volume, and the topic is a broad one, with new data always emerging; therefore, certain aspects, and sometimes the most recent information, may not be included. Chapters and sections 8. Uemura, M.
Nozaki, Y. Okawara, We are indebted to Drs.