(Hypertension. 1996;27:1337-1340.)
© 1996 American Heart Association, Inc.
Articles |
Renin Regulation in Cultured Proximal Tubular Cells
From the Department of Internal Medicine, University of Texas Southwestern Medical Center, and Department of Veterans Affairs Medical Center, Dallas.
Correspondence to William L. Henrich, MD, Department of Medicine, Medical College of Ohio, PO Box 10008, Toledo, OH 43699-0008. E-mail whenrich@vortex.mco.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Recent studies have documented the presence of a complete renin-angiotensin system in the proximal tubule of the kidney; however, little is known about the regulation of renin in this proximal tubular system. Therefore, we performed the present studies to learn whether the behavior of the renin system in cultured proximal tubule is similar to that of the juxtaglomerular renin system. Basal renin secretion from rabbit proximal tubular cells in primary culture was low and not affected by isoproterenol (10-5 mol/L), diltiazem (10-5 mol/L), or a zero-calcium bath (0 nmol/L). Only the calcium ionophore A23187 (10-4 mol/L) significantly reduced renin secretion in these cells (from 2.44±0.37 to 1.14±0.08 ng angiotensin I/mg protein per hour, P<.05). When the proximal tubular cells were lysed so the effects of the test agents on intracellular renin content could be assessed, isoproterenol caused a significant twofold (107%) increase (from 2.02±0.56 to 4.18±0.81 ng angiotensin I/mg protein per hour, P<.05), whereas diltiazem, A23187, and zero- and high-calcium baths did not produce a significant change. The effects of these agents on renin mRNA were examined in rabbit and rat proximal tubular cells in primary culture with the use of an S1 nuclease protection assay. Densitometry analysis of renin mRNA and either GAPDH mRNA (rat) or
-actin (rabbit) showed no significant alterations in renin
mRNA abundance. In summary, these results confirm the presence of renin
mRNA in cultured proximal tubular cells and suggest that a
low-level, constitutive secretion of renin occurs in this system
that is decreased by A23187. Moreover, the results also suggest that
proximal tubular renin is regulated, albeit differently from the
juxtaglomerular renin system. Finally, short-term
increments in proximal tubular renin occur without a change in renin
mRNA.
Key Words: kidney tubules, proximal • secretions • RNA, messenger • renin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Angiotensin II is a powerful hormone acknowledged to have a key regulatory influence over NaCl and NaHCO3 absorption in the PT of the kidney.1 In addition to this involvement in volume regulation, Ang II has also been identified as a growth factor for the PT2 and a stimulus for immunogenesis and may be a central factor in the pathogenesis of renal cysts.3 Given the central importance of Ang II in volume homeostasis, both the origin and regulation of Ang II in the PT have been topics of considerable recent interest and investigation.
Earlier micropuncture experiments suggested that the luminal concentration of Ang II increases along the length of the PT, a finding consistent with generation of Ang II by the PT.4 Since angiotensinogen protein, mRNA, and ACE have been identified in the PT cell,5 6 7 8 renin had been, until recently, the only missing component for a complete RAS in the PT. We9 and others10 have reported a time-dependent increase in renin-like activity in PT cells in primary culture. In addition, we have identified renin mRNA in primary cultures of PT cells and microdissected rat PT segments using reverse transcription–polymerase chain reaction,9 a finding recently confirmed by Chen et al.11 In our earlier study, renin mRNA was more easily detected after pretreatment of rats with the ACE inhibitor captopril in PTs, strongly suggesting that renin expression in this nephron segment is regulated.9
The identification of renin in the PT and the finding that its expression is regulated raise the questions of similarities to and differences from other renin systems in the kidney and vasculature. For example, the great majority of renin in the kidney is synthesized in granular JG cells located in the afferent arteriole.12 13 A maneuver such as ACE inhibitor administration seems to activate both the JG and PT RAS.9 However, the data of Braam et al14 suggest that the PT RAS may be regulated differently from the JG RAS. Renin secretion from JG cells has been well described: Renin release from these cells is largely regulated by intracellular calcium and cAMP, such that a decline in intracellular calcium or an increase in cAMP stimulates renin secretion in JG cells.12 15 16 17 We performed the present experiments in PT cells in primary culture to learn whether the PT renin system behaves in a manner similar to that of the JG cell renin system.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cell Culture and Incubations
Studies were performed in both rabbit and rat renal PT cells grown in primary culture, as previously described.9 18 Renin release and content studies were performed in rabbit PT cells. Renin mRNA measurements were made in both rabbit and rat PT cells. Briefly, 4- to 6-week-old male New Zealand White rabbits were killed by decapitation, and cortical sections were digested with 0.1% collagenase and centrifuged through an isosmotic 50% Percoll gradient. The PTs were recovered from the F4 fraction as described by Vinay et al.19 Tubules were inoculated and cultured in 1:1 Dulbecco's modified Eagle's medium (DMEM)/Ham's F-12 supplemented with 5 µg/mL insulin, 50 nmol/L hydrocortisone, 35 µg/mL transferrin, 29 nmol/L sodium selenite, 20 µmol/L ethanolamine, 1.5 mmol/L glutamine, 2 mmol/L calcium, and 100 µg/mL streptomycin. For the first 3 days of culture, 3% fetal bovine serum was added to the medium. Thereafter, medium was changed on alternate days until the cells reached confluence in 2 weeks; insulin and hydrocortisone were removed for 2 days before study.
The isolation of rat PTs was performed by modification of the methods of Vinay et al.19 Briefly, six to eight male Sprague-Dawley rats (Sasco Inc, Omaha, Neb) (150 to 175 g, 4 to 5 weeks old) were killed. The kidneys were removed with sterile technique, decapsulated, and rinsed in cold Hanks' balanced salt solution (HBSS) (Sigma Chemical Co). The cortex was removed and placed in a sterile glass Petri dish and minced with a single-edged razor. The tissue was incubated at 37°C for 1 hour in oxygenated HBSS containing 1 mg/mL type I collagenase (Sigma). After incubation, the digested tissue was filtered with a 53-µg filter and washed two times with cold HBSS and centrifuged at 500g at 4°C for 5 minutes (Fisher Scientific). The pellet was resuspended and washed with DMEM/F-12 medium containing 10% fetal calf serum and centrifuged at 500g at 4°C for 5 minutes. The cells were then placed on a 10% to 35% discontinuous Percoll (Sigma) gradient and centrifuged at 25 000g for 60 minutes at 4°C. After centrifugation, the cellular mixture separated into distinct bands. The PT cells were obtained from the third band, washed in fresh DMEM/F-12 medium containing 10% fetal calf serum, and plated.
Renin Release and Content
Renin activity was assayed in triplicate as the rate of
generation of Ang I from angiotensinogen by the
antibody-trapping method of Poulsen and Jorgensen as previously
described.20 21 Renin secretion was defined as renin
activity in the supernatant of cultured PT cells. In these studies,
prewarmed DMEM/F-12 medium was incubated with PT monolayers for 6 hours
and retrieved for renin activity assay. The zero-calcium bath
contained no added calcium but was otherwise identical to the
incubation buffer. The high-calcium bath contained 4 mmol/L
calcium. Intracellular renin content was defined as renin activity in
the cell lysate after removal of the medium.
In these studies, PT cells were pretreated with either control medium or medium containing isoproterenol (10-5 mol/L), diltiazem (10-5 mol/L), A23187 (a calcium ionophore, 10-4 mol/L), or a zero- or high-calcium bath. The concentrations of these agents were selected on the basis of their known effects on JG cell renin release.12 15 16 22 The cells were incubated for 6 hours, washed with buffered saline, and then lysed by addition of distilled water. Both renin secretion and cell renin content are expressed as nanograms Ang I generated per nanogram protein per hour of cellular protein as determined by the method of Lowry et al.23 Seven incubations were analyzed for each test agent.
S1 Nuclease Protection Assay
Total cellular RNA was isolated as previously
described.9 Cells were homogenized in
guanidinium thiocyanate, centrifuged through a CsCl cushion,
and further purified with phenol chloroform extraction and ethanol
precipitation. Since there is a low abundance of renin message in PT
cells, the sensitive S1 nuclease protection assay was
performed.24 Briefly, a uniformly 32P-labeled,
single-strand antisense renin DNA probe was generated with an
arithmetic polymerase chain reaction on cDNA templates linearized by
restriction endonucleases.25 The primers used for each of
the probes were as follows: rat renin S1,
TCAGTCCCATTCTCCATGTAGC-3' (425 bp); rabbit renin S1,
GAGGATGTGGTCAAAGAC-3' (542 bp); and rat GAPDH,
5'-GTCATATTCTCGTGGTTCAC-3' (500 bp). The labeled probes were separated
from the template by polyacrylamide/urea gel electrophoresis
and retrieved by electroelution. Twenty thousand counts of renin and
the normalization probe (either ß-actin or GAPDH) were mixed with
10 µg total RNA per sample, and the mixture was coprecipitated and
resuspended in 25 µL of 80% deionized formamide, 40 mmol/L HEPES (pH
6.5), 1 mmol/L EDTA, and 400 mmol/L NaCl. After overnight annealing at
42°C, S1 digestion was initiated at 42°C for 1 hour and
30 minutes with 300 U of S1 nuclease enzyme. Digested
samples were fractionated on a polyacrylamide (6%)/urea (7
mol/L) gel, and signals were determined by
autoradiography and densitometry (Hoeffer
Scientific). Six incubations for each test agent were
analyzed.
Data are mean±SE. Statistics were performed with Scheffé's ANOVA.26 A value of P<.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Renin Secretion Studies
The results of the 6-hour incubations in isolated rabbit PT cells are shown in Fig 1
. As can be seen, the addition of
isoproterenol or diltiazem or adjustment of the calcium concentration
in the media did not significantly affect renin secretion. However, the
addition of the calcium ionophore A23187 decreased renin secretion
significantly by 53% (from 2.44±0.37 to 1.14±0.08 ng Ang I/mg
protein per hour, P<.05).
|
, 4 mmol/L), and zero-calcium bath (Ca
, 0 mmol/L) did not
alter renin secretion from cultured PT cells. The calcium ionophore
A23187 (10-4 mol/L) decreased renin
secretion significantly, by 53% (*P<.05). Seven
incubations were used for each comparison. AI indicates Ang I.
Intracellular Renin Content
As shown in Fig 2 and in contrast to the renin
secretion studies, the addition of isoproterenol to the incubation
medium significantly increased intracellular renin content by twofold
(107%) at 6 hours (from 2.02±0.56 to 4.18±0.81 ng Ang I/mg protein
per hour, P<.05). The other agents and bath adjustments did
not affect intracellular renin content. Both diltiazem and a
zero-calcium bath increased intracellular renin content moderately
from control (34% and 38%, respectively), but these changes were not
statistically significant.
|
Effect of Agents and Incubations on Renin mRNA
The effects of all of the different incubations on renin and GAPDH
mRNA are shown in Fig 3. Densitometry analysis,
comparing changes in rat renin mRNA and GAPDH mRNA, confirmed that no
significant alterations in renin mRNA abundance occurred. Similar
results were observed in rabbit proximal convoluted tubular cells in
which renin mRNA was normalized to -actin (data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Although renin mRNA expression in the PT of the kidney is low,9 11 the finding that renin is synthesized in this location of the nephron is intriguing for several reasons. First, the PT contains an autocrine/paracrine RAS potentially capable of regulating sodium absorption and cell growth.27 28 29 Second, some components of the PT renin system, such as angiotensinogen protein and mRNA, are regulated by sodium deprivation6 and captopril administration,9 suggesting that the system is not simply a constitutive system but is capable of responding to systemic perturbations to maintain sodium homeostasis. Finally, the RAS in the PT may play a role in both normal and abnormal physiological conditions, including conditions in which Ang II could be a growth factor, such as in cyst growth in autosomal dominant polycystic kidney disease.3
Despite the growing interest in the RAS in the PT, previous studies have not characterized the response of the system to known renin agonists or antagonists. In this regard, most of the prior literature on renin secretion characterizes second messengers involved in JG renin release.12 16 The JG cell renin system has been studied in a variety of different experimental preparations, including whole-kidney renin secretory rates,30 renal superficial cortical slices,31 and isolated JG cells.32 Several key factors appear to regulate the JG cell RAS. An increase in intracellular calcium inhibits renin secretion, whereas a decrease in intracellular calcium favors renin secretion; an increase in cAMP stimulates renin secretion, whereas an increase in cGMP inhibits in vitro renin secretion.12 15 20 We undertook the present studies to contrast the regulatory behavior of the recently identified PT RAS to what is known about the well-studied JG renin system.
PT cells in primary culture were chosen for study so that the direct effects of the agonists could be assessed. These cells have proved reliable for the expression of renin mRNA and renin activity. Recent studies by Chen et al11 suggest that the renin activity elaborated in PT cells is, in fact, due to renin and not other aspartyl peptidases. In our previous studies of PT cells, we excluded the possibility of JG cell contamination of the primary culture by attempting to grow JG cells in the PT cell media for 14 days; however, JG cells are too fastidious and were not detectable after 5 days.9
The results of the various incubations suggest that the PT renin system is regulated differently from the JG system. First, there is little spontaneous renin secretion from these cells compared with JG cells. Second, even under the powerful influence of isoproterenol, diltiazem, or a zero-calcium bath, all agonists for renin secretion in JG cells, renin secretion did not occur. Of interest is the fact that the addition of the calcium ionophore A23187 did significantly reduce what would appear to be constitutive renin release.
In sum, rabbit PT cells in culture appear to have a constitutive renin release only partly responsive to changes in intracellular calcium. It is possible that the concentrations of agents tested in these studies were insufficient to provoke a response; however, the doses tested were chosen because of past experience with these agents in JG renin release.12 16 22
A second difference in the PT renin system is that although renin
secretion did not occur with isoproterenol, an increase in cellular
renin content did (Fig 2
). This would imply that a positive
ß-adrenergic response is capable of occurring in these cells.
This finding may have physiological relevance
because Ang II could be generated intracellularly and then either
elicit an effect in the cell or be elaborated into the tubular lumen.
Since angiotensinogen and ACE are present along the
apical membrane border of PT cells,33 Ang II could also be
produced at this location. Notably, the other renin agonists and
antagonists tested did not significantly alter the renin
content of PT cells, although both diltiazem and the zero-calcium
bath tended to increase renin content.
The results suggest that ß-agonists (and cAMP) are capable of regulating renin activity in the PT cell. They also suggest that intracellular calcium plays a less pivotal role in PT renin regulation than it does in the JG cell.
In these studies, renin mRNA expression was unchanged by any of the
agents or baths tested (Fig 3). Even in PT cells treated with
isoproterenol, in which renin content was increased by 107%, renin
mRNA clearly did not change. One interpretation of this finding is that
short-term ß-adrenergic stimulation enhances renin
biosynthesis without increasing renin gene transcription or transcript
half-life. A single systemic bolus of isoproterenol causes renin to
be released from JG cells into the systemic circulation, and the
released renin can be replenished without changes in renin
mRNA.34 In our previous study in whole animals, a 5-day
course of ACE inhibitor administration significantly
increased renin mRNA in microdissected rat PTs.9
Recent preliminary studies showed that PT renin mRNA is downregulated in rats several weeks after uninephrectomy.35 These preliminary studies distinctly showed that PT renin is regulated at the mRNA level in different chronic physiological models. In the present studies with the PT cell culture model, isoproterenol was applied to the cells for 6 hours. It is possible that longer incubations with ß-adrenergic agonists may eventually turn on renin gene expression. A biphasic response has been postulated in JG cells, in which short-term rapid changes in renin synthesis and release are regulated at translational and posttranslational levels, whereas long-term changes are associated with modulations of renin mRNA.34 36
In summary, we designed the present experiments to test the ability of known stimulators and inhibitors of the JG renin system on the recently identified RAS in the PT cell. The results show that in the rabbit PT cell in primary culture, a low level of renin secretion exists that is largely constitutive. Intracellular renin accumulation occurs in the PT cell on acute exposure to ß-agonists, presumably via a posttranscriptional mechanism. Finally, the role of changes in intracellular calcium seems much less important in the regulation of renin in the PT cell compared with the JG cell.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
Funding for these studies was provided by the Veterans Affairs Research Service and National Institutes of Health (1 RO1 HL-48960-01). The authors thank Dr Victor Lin for his assistance with the S1 nuclease experiments. The authors also thank Dr Robert Alpern for providing the rabbit PT cells in primary culture. Julie Propes and Carol Gannon provided expert secretarial assistance.
Received August 21, 1995; first decision October 2, 1995; accepted January 9, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Alpern RJ. Cellular mechanisms of proximal tubule acidification. Physiol Rev. 1990;70:1-26.
2. Woolf G, Neilson E. Angiotensin II as a hypertrophic cytokine for proximal tubule cells. Kidney Int. 1993;43:S100-S107.
3. Torres VE, Donovan KA, Scicli G, Holley KE, Thibodeau SN, Carretero OA, Inagami T, McAteer JA, Johnson CM. Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease. Kidney Int. 1992;42:364-373. [Medline] [Order article via Infotrieve]
4. Seiklay MG, Arant BS, Seney FD. Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest. 1990;86:1352-1357.
5. Campbell DJ, Habener JH. Regional distribution of angiotensinogen messenger RNA in rat adrenal and kidney. J Hypertens Suppl. 1987;4:S385-S387.
6. Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ. In situ hybridization evidence for angiotensinogen mRNA in the rat proximal tubule: an hypothesis for the intrarenal renin angiotensin system. J Clin Invest. 1990;85:417-423.
7. Marchetti J, Rouseau S, Alhenc-Gelas F. Angiotensin I converting enzyme and kinin-hydrolyzing enzyme along the rabbit nephron. Kidney Int. 1987;31:744-751. [Medline] [Order article via Infotrieve]
8. Ward PE, Erdos EG, Gedney CD, Dowben RM, Reynolds RC. Isolation of membrane-bound renal enzyme that metabolized kinins and angiotensin. Biochem J. 1976;157:643-650. [Medline] [Order article via Infotrieve]
9. Moe OW, Ujii K, Star RA, Miller RT, Widell J, Alpern RJ, Henrich WL. Renin expression in renal proximal tubule. J Clin Invest. 1993;91:774-779.
10. Yanagawa N, Capparelli AW, Jo OD, Friedal A, Barrett B, Eggena P. Production of angiotensinogen and renin-like activity by rabbit proximal tubular cells in culture. Kidney Int. 1991;39:938-941. [Medline] [Order article via Infotrieve]
11. Chen M, Harris P, Rose D, Smart A, He X-R, Kretzler M, Briggs JP, Schermann J. Renin and renin mRNA in proximal tubules of the rat kidney. J Clin Invest. 1994;94:237-243.
12. Churchill PC. Second messengers in renin secretion. Am J Physiol. 1985;249:F175-F184.
13.
Lutterotti N, Catanzaro DF, Sealey JE, Laragh
JH. Renin is not synthesized by cardiac and extrarenal vascular
tissues. Circulation. 1994;89:458-470.
14.
Braam B, Mitchell KD, Fox J, Navar LG. Proximal
tubular secretion of angiotensin II in rats.
Am J Physiol. 1993;264:F891-F898.
15. Henrich WL. Prostaglandins in renin secretion. Kidney Int. 1981;19:822-830. [Medline] [Order article via Infotrieve]
16. Davis JO, Freeman RH. Mechanisms regulating renin secretion. Physiol Rev. 1970;56:1-56.
17.
Henrich WL, Campbell WB. Importance of calcium
in renal renin release. Am J Physiol. 1986;251:E98-E106.
18.
Horie S, Moe O, Trejedor A, Alpern RJ.
Preincubation in acid medium increases Na/H antiporter activity in
cultured renal proximal tubule cells. Proc Natl Acad Sci
U S A. 1990;87:4742-4745.
19. Vinay P, Gougoux A, Lemieux G. Isolation of a pure suspension of rat proximal tubules. Am J Physiol. 1981;10:F403-F411.
20. Henrich WL, McAllister EA, Smith PB, Campbell WB. Guanine 3',5'-cyclic monophosphate as a mediator of inhibition of renin release. Am J Physiol. 1988;24:F474-F478.
21.
Poulsen K, Jorgensen K. An easy
radioimmunological microassay of renin activity, concentration, and
substrate in human and animal plasma and tissues based on
angiotensin I trapping by antibody. J
Clin Endocrinol Metab. 1974;39:816-819.
22.
Henrich WL, Campbell WB. Relationship between
prostaglandins and the beta-adrenergic pathway to renin
secretion: an in vitro study. Am J Physiol. 1984;247:E343-E348.
23.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.
Protein measurement with the Folin phenol reagent.
J Biol Chem. 1951;193:265-275.
24. Berk AJ, Sharp PA. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell. 1977;12:721-732. [Medline] [Order article via Infotrieve]
25. Blakeley MS, Carman MD. Generation of an S1 probe using arithmetic polymerase chain reaction. Biotechniques. 1991;10:52-53. [Medline] [Order article via Infotrieve]
26. Scheffé H. The Analysis of Variance. New York, NY: John Wiley & Sons; 1959.
27. Cano A, Miller RT, Alpern RJ, Preisig PA. Angiotensin II stimulation of Na-H antiporter activity is cAMP independent in OKP cells. J Am Soc Nephrol. 1991;2:450. Abstract
28.
Geibel J, Geibisch G, Boron WF.
Angiotensin II stimulates both Na/H exchange and
Na/HCO3 cotransport in the rabbit proximal tubule.
Proc Natl Acad Sci U S A. 1990;87:7917-7920.
29.
Saccomani GK, Mitchell D, Navar LG.
Angiotensin II stimulation of Na/H exchange in proximal
tubule cells. Am J Physiol. 1990;258:F1188-F1195.
30. Berl T, Henrich WL, Erickson AL, Schrier RW. Prostaglandins in the beta-adrenergic and baroreceptor mediated secretion of renin. Am J Physiol. 1979;236:F472-F477.
31. Henrich WL, McAllister EA, Smith PB, Campbell W. Importance of cyclic GMP in the renin-inhibitory signal. Am J Physiol. 1988;24:F474-F478.
32.
Moe O, Tejedor A, Campbell W, Alpern RJ, Henrich
WL. Effects of endothelin on in vitro renin release.
Am J Physiol. 1991;260:E521-E525.
33. Moe O, Alpern RJ, Henrich WL. The renal proximal tubule renin angiotensin system. Semin Nephrol. 1993;13:525-557.
34.
Dzau V, Bury DW, Pratt RE. Molecular biology of
the renin-angiotensin system. Am J
Physiol. 1988;255:F563-F573.
35. Tank JE, Moe OW, Star RA, McAllister EA, Eskue A, Henrich WL. Differential regulation of the glomerular, proximal tubule and juxtaglomerular renin-angiotensin systems in uninephrectomy. J Am Soc Nephrol. 1994;5:671. Abstract.
36.
Nakamura N, Soubrier F, Menard J, Panthier JJ, Rougeon
F, Corvol P. Nonproportional changes in plasma renin
concentration, renal renin content, and rat renin messenger RNA.
Hypertension. 1985;7:855-859.
This article has been cited by other articles:
 |
|
 |
|
  N. Ohashi, T. Yamamoto, Y. Huang, T. Misaki, H. Fukasawa, H. Suzuki, A. Togawa, S. Suzuki, Y. Fujigaki, T. Nakagawa, et al. Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1512 - F1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Markus, C. Goy, D. J. Adams, F. J. Lovicu, and B. J. Morris Renin Enhancer Is Crucial for Full Response in Renin Expression to an In Vivo Stimulus Hypertension, November 1, 2007; 50(5): 933 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kobori, M. Nangaku, L. G. Navar, and A. Nishiyama The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease Pharmacol. Rev., September 1, 2007; 59(3): 251 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hartner, M. Porst, B. Klanke, N. Cordasic, R. Veelken, and K. F. Hilgers Angiotensin II formation in the kidney and nephrosclerosis in Ren-2 hypertensive rats Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1778 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Prieto-Carrasquero, H. Kobori, Y. Ozawa, A. Gutierrez, D. Seth, and L. G. Navar AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats Am J Physiol Renal Physiol, September 1, 2005; 289(3): F632 - F637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Terebessy, A. Masszi, A. Fintha, A. Sebe, T. Huszar, L. Rosivall, and I. Mucsi Angiotensin II activates the human renin promoter in an in vitro model: the role of c-Jun-N-terminal kinase Nephrol. Dial. Transplant., September 1, 2004; 19(9): 2184 - 2191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Prieto-Carrasquero, L. M. Harrison-Bernard, H. Kobori, Y. Ozawa, K. S. Hering-Smith, L. L. Hamm, and L. G. Navar Enhancement of Collecting Duct Renin in Angiotensin II-Dependent Hypertensive Rats Hypertension, August 1, 2004; 44(2): 223 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ingert, M. Grima, C. Coquard, M. Barthelmebs, and J.-L. Imbs Effects of dietary salt changes on renal renin-angiotensin system in rats Am J Physiol Renal Physiol, November 1, 2002; 283(5): F995 - F1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Navar, L. M. Harrison-Bernard, A. Nishiyama, and H. Kobori Regulation of Intrarenal Angiotensin II in Hypertension Hypertension, February 1, 2002; 39(2): 316 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L G. Navar, K. D Mitchell, L. M Harrison-Bernard, H. Kobori, and A. Nishiyama Review: Intrarenal angiotensin II levels in normal and hypertensive states Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S176 - S184. [PDF]
|
|
|
|
 |
|
 V. F. Norwood, M. Garmey, J. Wolford, R. M. Carey, and R. A. Gomez Novel expression and regulation of the renin-angiotensin system in metanephric organ culture Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R522 - R530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rohrwasser, T. Morgan, H. F. Dillon, L. Zhao, C. W. Callaway, E. Hillas, S. Zhang, T. Cheng, T. Inagami, K. Ward, et al. Elements of a Paracrine Tubular Renin-Angiotensin System Along the Entire Nephron Hypertension, December 1, 1999; 34(6): 1265 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Anderson, S. Martin, J. L. Berka, D. E. James, J. W. Slot, and J. L. Stow Distinct localization of renin and GLUT-4 in juxtaglomerular cells of mouse kidney Am J Physiol Renal Physiol, January 1, 1998; 274(1): F26 - F33. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||