 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
REVIEW |
,||
*
Department of Human Genetics, University of Utah School of Medicine, Salt
Lake City, Utah.
Howard Hughes Medical Institute, University of Utah School of Medicine,
Salt Lake City, Utah.
Department of Pathology, University of Utah School of Medicine, Salt Lake
City, Utah.
§
Department of Obstetrics and Gynecology, University of Utah School of
Medicine, Salt Lake City, Utah.
||
Department of Veterans Affairs, Salt Lake City, Utah.
Correspondence to Dr. Jean-Marc Lalouel, Howard Hughes Medical Institute, Eccles Institute of Human Genetics, 6th Floor, University of Utah Health Sciences Center, Salt Lake City, UT 84112. Phone: 801-581-4311; Fax: 801-587-9045; E-mail: jml{at}howard.genetics.utah.edu
 |
Abstract |
|---|
 Top Abstract IntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
|
Development of a Genetic Hypothesis |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
|
Studies of renin, using either biallelic markers (3) or a microsatellite (Jeunemaitre X, Soubrier F, Corvol P, Lalouel JM, unpublished observations), and angiotensin-converting enzyme (4) remained inconclusive. In contrast, significant genetic linkage was observed for angiotensinogen in two large series of independently ascertained sibling pairs, collected in Salt Lake City and Paris (5). In an attempt to define subsets with a greater likelihood of genetic determination, one of two criteria was used, i.e., the onset of hypertension before the age of 45 yr or the use of two antihypertensive medications (as a possible indicator of clinical severity). Greater statistical significance was achieved for each subset, despite the smaller sample sizes generated by these selection criteria. It was also noted that the greatest significance was achieved when the analysis was restricted to male siblings.
Angiotensinogen received less attention than other RAS components in previous genetic studies, despite warnings that it could well be an "underrated participant" in BP regulation and in the development of hypertension (6). It was not considered a candidate gene in early genetic studies of hypertensive rats. This relative lack of interest is attributable in part to the relative blandness of substrates, in contrast to enzymes. However, it also originates from the long-held view that angiotensinogen, which is present in plasma at concentrations long judged to be far in excess of the Km for its reaction with renin, could not contribute to BP regulation.
Allelic Association
Linkage between AGT and essential hypertension suggested that
genetic variations in the AGT gene may affect individual
predisposition to essential hypertension. The AGT gene was scanned
for the presence of such variation, and the frequencies of common genetic
polymorphisms were compared between case and control subjects. Case subjects
consisted of a proband randomly selected from each sibship with multiple
hypertensive patients, whereas control subjects were selected from
normotensive reference populations. The most significant observation was that,
at residue 235 of angiotensinogen, an allele encoding the presence of
threonine (T235) instead of methionine (M235) was more
frequent among case subjects than among control subjects
(Figure 2A). This association
was significant for both the Salt Lake City and Paris samples. Plasma
angiotensinogen levels were measured for study subjects, affording a test of
association with the T235/M235 polymorphism. Plasma angiotensinogen
levels varied significantly with genotype, with T235 homozygotes
exhibiting approximately 20% higher levels than M235 homozygotes
(5). Statistical association
indicates only correlation; therefore, those studies could not establish
whether T235 directly imparted disease predisposition or was only a
marker for other, unidentified, variations in the gene.
|
Genetic linkage and allelic association of an AGT variant with both essential hypertension and plasma angiotensinogen levels in two independent samples suggested that individual differences in the gene might contribute to disease development. Linkage analysis of another Caucasian sample provided consistent results (7,8). When data from nine European centers were pooled, however, no significant evidence of linkage could be obtained (9). The increased power expected for a larger sample may have been offset by increased heterogeneity of the patient populations sampled. Various attempts to replicate the association have been reported, with mixed results. Those studies were the subject of two meta-analyses, which confirmed significance in the aggregate and discussed features that affected the varying outcomes of the studies (10,11). These issues have been addressed by Corvol et al. (12).
Association with Essential Hypertension in the Japanese
Population
An angiotensinogen-mediated predisposition to essential hypertension would
be expected to affect sodium homeostasis and the regulation of fluid volume.
Given the high prevalence of essential hypertension in Japan and the likely
significance of dietary sodium for this population, a study was undertaken to
test the association between T235 and essential hypertension among
Japanese subjects. An initial report
(13) revealed that
T235 occurred at high frequency among Japanese subjects and was
indeed associated with essential hypertension
(Figure 2B). With one exception
(14), subsequent studies in
Japan have confirmed this association
(15,16,17).
Association with Preeclampsia
Plasma angiotensinogen levels increase severalfold in estrogenic states
such as pregnancy or oral contraceptive use, and hypertension may be induced
by such states. Indeed, pre-eclampsia is a common form of pregnancy-induced
hypertension that has long been considered to involve a significant but
unknown genetic component. T235 occurred at higher frequency among
Caucasian women with preeclampsia than among control subjects, a finding that
was corroborated in a small Japanese sample
(18). This observation was
confirmed in a larger sample of Caucasian patients (K. Ward, unpublished
observations).
Haplotype Studies
If T235 serves only as a marker for one or more unknown functional
variants in the gene, stronger association may be observed for subsets of
T235 alleles defined through variations occurring at other sites in
the gene. Common biallelic polymorphisms were identified by screening a
1200-nucleotide segment of the AGT promoter, all exons, the
intron-exon junctions, and the 3'-untranslated segment of the gene.
These segments were also sequenced for 16 individuals homozygous for
T235 alleles. Multiple polymorphisms that occurred non-randomly, and
thus generated a limited number of haplotypes, were observed
(19). The T235
alleles were subdivided into five subsets, whereas only one common variation
subdivided the M235 allele (Figure
3). None of the subsets exhibited greater association with
hypertension than that observed for T235 alone.
|
Another feature of this investigation of genetic polymorphism was the observation that several variants occurred in quasi-complete association. In particular, with few exceptions, T235 occurred with adenine (A) at position -6, whereas M235 occurred with guanine (G) at position -6. Therefore, all associations reported for T235 directly extend to A(-6).
|
Development of a Molecular Hypothesis |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
The only well defined function of angiotensinogen is its role as a hormone
precursor, serving as a substrate for renin in the formation of angiotensin I
(AngI). On the basis of its sequence similarity, the protein belongs to the
family of serine protease inhibitors, or serpins. The family includes
inhibitors such as 
1-antitrypsin and antithrombin III but also includes
proteins that do not exhibit an inhibitor function, such as ovalbumin.
Although there is no direct evidence that angiotensinogen can serve as a
serine protease inhibitor, the matter has been the subject of repeated
investigations (20).
The substitution of threonine for methionine at codon 235 does not, by
itself, provide any functional clue. This residue occurs in a segment of the
protein that demonstrates little conservation across species. Although the
three-dimensional structure of angiotensinogen has not been established, some
features can be inferred from consideration of the structures of other
serpins, such as 1-antitrypsin and antithrombin III
(21). Codon 235 seems to occur
in a part of the molecule that is not in close proximity to the amino terminus
of the protein that encodes AngI. Structural models of renin complexed with
peptide inhibitors demonstrate that the substrate assumes an extended
conformation in the active cleft of the enzyme
(22), which suggests that the
amino-terminal portion of angiotensinogen protrudes in solution, with little
secondary structure.
It remains conceivable that the T235/M235 polymorphism affects angiotensinogen function indirectly, by affecting protein conformation or glycosylation. To test this hypothesis, the protein, with either threonine or methionine at codon 235, was transiently expressed in cultured mammalian cells. Pulse-chase experiments demonstrated no difference between the two proteins with respect to glycosylation, secretion, or stability. Furthermore, the substitution had no detectable effect on the kinetics of enzymatic cleavage of the protein by purified recombinant human renin (23).
The T235/M235 polymorphism could also affect other biochemical characteristics and functions of angiotensinogen. A cysteine residue at position 232 may be involved in complex formation with other proteins, a process that may be differentially affected by the T235/M235 polymorphism (24). It has also been suggested that angiotensinogen may have a reactive center that mediates a serine protease inhibitor function (20); in vitro evidence was recently presented (25).
Testing of the Significance of Promoter Variants In Vitro
The G(-6)/A(-6) polymorphism occurs in the core promoter of the
angiotensinogen gene. Mutations in such a gene region could affect DNA
interactions with factors involved in transcription initiation and could thus
affect the rate at which the gene is expressed. Markedly reduced expression of
a reporter gene in HepG2 cells after removal of the residues from position -16
to position +44 indicated the critical significance of this segment of the
AGT promoter (26).
Other experiments have led to the suggestion that a ubiquitous transcription
factor that binds to a segment of the mouse promoter spanning residues -6 to
+22 could be an important determinant of transcriptional activity
(27).
To test the significance of the G(-6)/A(-6) polymorphism in angiotensinogen expression, fusion genes were generated by placing a reporter gene (luciferase) under the control of segments of the human angiotensinogen promoter spanning either nucleotides -256 to +90 or nucleotides -70 to +90. Such fusion genes with either variant were transiently expressed in two types of mammalian cells, i.e., HepG2 and HEK293, which are transformed human hepatocyte and embryonic kidney cell lines, respectively. A large number of parallel experiments were performed in quadruplicate, using a variety of controls, to ensure the validity of the experimental comparisons. Further validation was provided by mutagenesis studies.
These experiments revealed consistent effects of the nucleotide substitution at position -6 on the transcriptional activity of the reporter (Figure 4). The differences observed were highly statistically significant, with significance levels ranging from 10-8 to 10-16. The magnitude of the observed effect, however, was modest; differences ranged from 20 to 50% when expressed on the observed scale of reporter activity, with A(-6) exhibiting greater activity than G(-6). Compared with effects typically analyzed in the transcription field, where losses or gains of certain DNA-protein interactions are examined, this seems to be a small effect. It is also small compared with the large differences noted between experiments, because the design affords little control of factors affecting transfection efficiency. If we follow the convention of expressing the data after standardization within experiments, the substitution effect can be expressed relative to its SD (as determined by t test). The differences noted were equal to or exceded 2 SD units (Figure 4). For statisticians, the magnitude of the difference between two means can be ascertained only by reference to the SD of the observations. When the data are considered in that context, the high level of significance observed reflects the high statistical power afforded by extensive experimental replication (23).
|
The differences in promoter activity associated with the nucleotide substitution suggested that the substitution could affect interactions with nuclear proteins involved in transcriptional control. DNA binding studies provided support for such specific interactions (23). The identification of specific factors that bind to this region of the gene could prove challenging, however, given the relatively low affinities revealed in these experiments.
This work illustrates some of the unique challenges that face investigators who attempt to elucidate the genetic determinants of common diseases. Graded differences that affect homeostatic regulation are not expected to produce the clear-cut qualitative differences that accompany mutations that produce gain or loss of function. It is also clear that causality cannot be inferred from such experiments. The novel observation that an additional common polymorphism at nucleotide 67 is in complete association with both the G(-6)/A(-6) and M235/T235 polymorphisms (28) (Rohrwasser A, Lalouel JM, unpublished observations) further emphasizes this point. Because this polymorphism was also present in our expression studies (23), our published results reflect the compound effects of joint substitutions at nucleotides -6 and 67. In preliminary experiments, substitution at either site appears to affect transcription in vitro.
In Vivo Correlations
These promoter transactivation experiments support the conclusion that
naturally occurring variations in the AGT promoter can affect basal
transcription in vitro. As noted, "it is clearly not possible
to directly extend the results of transfection experiments done with truncated
AGT promoters in cultured cells to the function of an intact
AGT gene at the level of the whole organism"
(23). Two independent lines of
evidence provide support for this hypothesis, however.
Smithies and colleagues (29,30) have provided direct evidence that a modest increase in AGT expression can lead to both increased plasma angiotensinogen levels and increased AP. Those authors used homologous recombination to inactivate or generate targeted gene duplication of the AGT gene in mice, generating animals with zero to four functional AGT genes. Of particular significance in the present context was the observation that animals with three functional AGT genes exhibited 10 to 20% elevations in plasma angiotensinogen levels and AP, compared with animals with two unaltered genes (Figure 5). The transgenic approach demonstrated a direct causal link between increased AGT expression and elevated BP. Furthermore, it demonstrated that a difference in expression of no more than 50% was sufficient to produce a detectable difference in AP.
|
The complete association between the polymorphism at nucleotide -6 and that at codon 235 suggested that the latter variation, which is present in transcribed mRNA, could serve as a marker to test for effects of the former on gene expression in tissue extracts. Although liver tissue was not readily available to us for this purpose, we had access to decidual tissue collected from women who had undergone elective abortions in the first trimester of pregnancy. We observed that, in human decidua, AGT expression was restricted to the smooth muscle cells of the spiral arteries (31). Total RNA isolated from decidual tissue from 39 women with the heterozygous M235/T235 genotype was tested for differential representation of AGT mRNA carrying either allele, using two different procedures, i.e., an allele-specific ligation assay and a single-nucleotide primer extension assay (31). Both assays revealed a significant excess of mRNA with T235 over mRNA with M235, providing an in vivo correlation in support of our hypothesis.
Molecular Hypothesis
The experimental evidence accumulated thus far affords the delineation of a
working hypothesis. This hypothesis states that individual variations in the
AGT gene that are associated with naturally occurring variations at
nucleotides -6 and 67 and codon 235 impart modest differences in AGT
gene expression. Individuals with the A(-6), C67, and T235
alleles may exhibit increased basal expression of the gene, which with time
may lead to elevated baseline AP, compared with individuals without these
alleles. The hypothesis that a chronic difference in AGT expression
can lead to hypertension is supported by the animal experiments reported by
Smithies and colleagues
(29,30).
|
Significance of Angiotensinogen in Circulatory Homeostasis |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
Similarly, it is not altogether surprising that the actual molecular variants involved in the angiotensinogen gene, and the manner in which they affect circulatory homeostasis, cannot be established from direct observation of the mutation. Nonsense mutations, which signal gain or loss of function in classic mendelian disorders, were not found in the gene, nor were they expected for a genetic determinant of a common disease that must be both frequent in the population and of limited physiologic significance.
The molecular hypothesis outlined above suggests that genetic variations may affect angiotensinogen gene expression. It provides few clues, however, regarding the physiologic processes affected by the molecular variations observed in human subjects. To better understand the functional significance of individual variations for angiotensinogen expression, knowledge must advance at two levels, as follows. What physiologic functions are affected by changes in angiotensinogen expression? In what cell, in what organ, and under what circumstances can such differences in expression ultimately affect AP?
Evidence that Changes in Angiotensinogen Concentrations Can Affect
the Rate of AngII Formation
The activity of the RAS depends on the rate of formation of AngII. Acute
stimulation or depression of the system is mediated primarily by regulation of
renin release and expression
(32). In contrast to renin,
the plasma concentrations of angiotensinogen vary slowly. However, in response
to stimulation by estrogens, glucocorticoids, or thyroid hormone, plasma
angiotensinogen levels can increase severalfold in 1 to 4 d. It was long
thought that angiotensinogen was present in plasma at concentrations far in
excess of the Km for its reaction with renin and that it
was therefore not an important determinant of AngII formation. In more recent
work performed with highly purified preparations of both enzyme and substrate,
it was recognized that the plasma concentration of angiotensinogen was close
to the Km for the reaction
(33). It follows that changes
in plasma angiotensinogen levels can indeed affect the rate of AngII
formation, with other factors being equal. Another recent argument supporting
the same conclusion is that, because of the high affinity but slow cleavage
rate for the reaction between angiotensinogen and renin, the concentration of
the former may affect the catabolism of the latter
(34).
Evidence that Chronic Elevations in AngII Formation Can Lead to
Increased AP
Angiotensinogen may contribute to AP regulation through extracellular fluid
volume control. Gene titration experiments demonstrated that moderate but
sustained increases in AGT expression led directly to increased AP
(29,30),
and kinetic considerations indicate that such increases could affect AngII
formation.
Proof that chronic infusion of AngII at subpressor doses can lead to progressive increases in AP has been provided (35,36). Guyton long ago suggested that the increases in AP resulted from sodium retention, concluding that "the sodium-retaining effect of angiotensin almost certainly results from a direct effect of angiotensin on the kidney itself" (37, p 191).
Effects on Systemic and Local RAS
The systemic RAS and multiple local RAS are involved in AP control
(32), and any of these systems
can be affected by variation in angiotensinogen expression. The correlated
increases in plasma angiotensinogen levels and AP observed in transgenic
animals as the number of AGT genes is increased do not necessarily
indicate a causal relationship between these two phenotypes. The detection of
abundant angiotensinogen mRNA in proximal tubule and its stimulation by
dietary salt
(38,39)
suggested a significant role for a local RAS in some aspects of proximal
tubule function.
Significance of AngII in Renal Function
There is considerable evidence that AngII of both intrarenal and
circulating origin affects renal function through effects on hemodynamics, the
regulation of glomerular filtration, or the regulation of sodium reabsorption.
Hall and Brands presented a very cogent review of the evidence supporting the
conclusion that "the direct intrarenal actions of angiotensin II play a
dominant role in long-term regulation of volume homeostasis and blood
pressure" (40). It is
often assumed that the sodiumretaining effects of AngII are mediated by
stimulation of aldosterone secretion. Experimental models, however,
convincingly demonstrated that, although minimal levels of aldosterone are
necessary for normal physiologic function, "changes in aldosterone
secretion are normally not essential in maintaining sodium balance or arterial
pressure during fluctuations in sodium intake"
(40).
High Luminal Concentrations of AngII in Proximal Tubule
The finding by Seikaly et al.
(41) that AngII is present in
the luminal fluid of proximal tubule at concentrations that exceed those in
plasma by at least 2 orders of magnitude suggested local formation of the
peptide. Because the high molecular weight of angiotensinogen precludes its
filtration through the glomerular membrane, tubular AngII is likely to be
derived from angiotensinogen synthesized in the proximal tubule. Braam et
al. (42) confirmed such
high AngII concentrations. They also demonstrated that AngI was present in
tubular fluid at concentrations similar to those of AngII. Local conversion is
likely, because high levels of angiotensin-converting enzyme in proximal
tubule have been reported
(43). Whether angiotensinogen
or angiotensin peptides are secreted by proximal tubule and whether filtered
or locally produced renin catalyzes the reaction remains unsettled, as
reviewed by Navar et al.
(44). Formation of AngII at
this site could be significant for the regulation of sodium reabsorption in
this proximal segment of the nephron. Angiotensin receptors have been observed
at both the basolateral and luminal sides of proximal tubule
(45). There is abundant
evidence that luminal AngII stimulates the apical sodium/hydrogen-exchanger
and possibly other transport systems in proximal tubule
(46).
Whether AngII exerts any effects in more distal segments of the nephron is less clear, although several arguments suggest that it might (40,44). At least one report indicates that it may affect sodium reabsorption by an amiloride-sensitive channel in early collecting tubule (47). Angiotensin-converting enzyme is found in luminal fluid as well as at the luminal surface of distal sites (43), and AngII receptors have been mapped along most of the nephron, with evidence for their presence on the luminal side being provided by immunocytochemical analyses (48).
|
Elements of a Paracrine System along the Entire Nephron |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
Using mice as an experimental model, we confirmed that angiotensinogen was expressed in proximal tubule, in a dietary sodium-dependent manner (38), and in no other tubular segments. The granular appearance of angiotensinogen in the vicinity of periodic acid-Schiff-counterstained brush borders in proximal tubule sections suggested a secretory process (Figure 6A). When confluent monolayers of conditionally immortalized murine proximal tubule cells (50) were grown on permeable membranes, angiotensinogen was reproducibly detected only in the apical chamber (Figure 6B). These in vitro data suggested secretion into the tubular lumen in vivo; some evidence for this process was previously provided by micropuncture data presented in abstract form (51). Because angiotensinogen is not filtered, indirect evidence for luminal secretion can be sought by testing for the presence of angiotensinogen in the final urine. Angiotensinogen was detected in the urine of mice and human subjects by an indirect immunoassay that measured uncleaved protein. No significant amounts of material could be detected for mice fed a high-sodium diet, whereas amounts reaching nanomolar concentrations were observed after sodium restriction. Taken together, these observations support the conclusion that angiotensinogen is secreted in the tubular fluid of proximal tubule, as a function of dietary sodium, and transits through the entire nephron. This contrasts with the fact that neither renin protein nor renin mRNA could be observed in proximal tubule under conditions of either high or low sodium intake, whether tissues or murine proximal tubule cells were examined.
|
Renin Expression in Connecting Tubule
The presence of angiotensinogen in tubular fluid throughout the nephron
could represent elimination or delivery to a distal site. Immunoreactive renin
has occasionally been noted in tubular segments
(52,53,54,55),
but those observations have been interpreted either as artifactual or as
evidence for nonspecific reuptake of filtered renin. We examined renin
distribution in the kidneys of animals after acute changes in dietary sodium
levels. In sodium-restricted animals, specific immunostaining was observed in
cortical clusters of open tubular segments that, on the basis of their
distribution and morphologic features, were identified as the arcades formed
by merging connecting tubules of midcortical and deep nephrons
(Figure 7A). Staining was
predominantly observed at the apical side of some of the cells in these
tubular sections. Staining for renin and H+-ATPase in consecutive
serial sections revealed that the two stains were mutually exclusive,
supporting the conclusion that renin expression was restricted to principal
cells of the connecting tubule (Figure
7B).
|
Local synthesis was demonstrated using two approaches, i.e., microdissection of tubular segments followed by reverse-transcription-PCR and in situ reverse transcription-PCR (49). For each approach, four independent experiments were performed and yielded concordant results. Detection of renin mRNA required induction by either acute sodium restriction or amiloride inhibition of sodium reabsorption in animals after the switch to a high-sodium diet. To obtain additional evidence for the local production of renin, segments of midcortical tubular arcades were microdissected from sodium-restricted animals and the cells were dissociated, washed, transferred to charged membranes, and probed for the presence of immunoreactive renin (56). Connecting tubule cells displayed immunoreactive halos similar to those observed for positive control cells (Chinese hamster ovary cells stably transformed for mouse renin), in contrast to negative control cells (Chinese hamster ovary cells stably transformed for human angiotensinogen) (49).
|
Significance of a Tubular RAS along the Entire Nephron |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
|
In proximal tubule, the partition of circulating and luminal angiotensinogen across the glomerular membrane contrasts with the filtration of systemic renin. This topographic organization affords both independent regulation of the rate of angiotensin formation through control of substrate availability in each compartment and coordinated regulation through delivery of active enzyme. Assuming that the dominant role of the circulating RAS is in regulating vascular tone, whereas that of AngII formation in proximal tubule is via its effect on bulk sodium reabsorption, this disposition may be critical for circulatory homeostasis, by affording coordinated regulation of both vascular tone and plasma volume.
The macula densa provides a mechanism to relate renin release by the juxtaglomerular apparatus into the circulation to sodium delivery downstream from the proximal tubule. Aspects of this feedback regulation have been well characterized (57). Although it is self-evident that sodium excretion depends on fine reabsorption in terminal segments of the nephron, it is unclear whether and how the RAS is involved. There is ample indirect evidence that intrarenal generation of AngII plays a critical role in circulatory homeostasis in response to changes in dietary sodium (40). The synthesis and secretion of renin in connecting tubules and the action of renin on luminal angiotensinogen originating in proximal tubule would allow AngII to participate in the regulation of sodium excretion through its effect on sodium reabsorption in the collecting duct. Interactions between substrate originating in proximal tubule and renin generated in connecting tubule may also provide a mechanism to coordinate bulk and fine sodium reabsorption at these two sites, in a manner that remains to be characterized. Although speculative, these considerations can serve as a basis for future experimental studies.
|
Conclusion |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionDevelopment of a Genetic...Development of a Molecular...Significance of Angiotensinogen...Elements of a Paracrine...Significance of a Tubular...ConclusionReferences |
|---|
structure of dimeric antithrombin.
Structure 2:257
-270, 1994[Medline]
This article has been cited by other articles:
 |
|
 |
|
  B. C. Rossier and L. Schild Epithelial Sodium Channel: Mendelian Versus Essential Hypertension Hypertension, October 1, 2008; 52(4): 595 - 600. [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Lalouel and A. Rohrwasser Genetic Susceptibility to Essential Hypertension: Insight From Angiotensinogen Hypertension, March 1, 2007; 49(3): 597 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Chelbi, F. Mondon, H. Jammes, C. Buffat, T.-M. Mignot, J. Tost, F. Busato, I. Gut, R. Rebourcet, P. Laissue, et al. Expressional and Epigenetic Alterations of Placental Serine Protease Inhibitors: SERPINA3 Is a Potential Marker of Preeclampsia Hypertension, January 1, 2007; 49(1): 76 - 83. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
HOME
CURRENT ISSUE
ARCHIVES
JASN Express
ONLINE SUBMISSION
AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP |
