| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
University of Montréal (S.-L.Z., X.C., J.G.F., J.S.D.C.), Maisonneuve-Rosemont Hospital, Research Center, Montréal, Québec, Canada H1T 2M4; Harvard Medical School (S.-S.T., J.R.I.), Massachusetts General Hospital, Pediatric Nephrology Unit, WAC 709, Boston, Massachusetts 02114-3117
Address all correspondence and requests for reprints to: Dr. John S. D. Chan, University of Montréal, Maisonneuve-Rosemmont Hospital, Research Center, 5415 boulevard de l’Assomption, Montréal, Québec, Canada, H1T 2M4.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Several studies have shown that incubation of murine proximal tubular cells in a high glucose (i.e. 25 mM) medium or in the presence of high levels of Ang II (i.e. 10-8 M) induces cellular hypertrophy and extracellular matrix protein synthesis (7, 8, 9, 10, 11, 12). We have previously reported that high levels of glucose stimulate the expression of the rat ANG gene in opossum kidney (OK) proximal tubular cells (13) and in IRPTC (14). This stimulatory effect of glucose is blocked in the presence of inhibitors of protein kinase C (PKC) and aldose reductase. These studies indicate that high levels of glucose may activate the local renal RAS via the stimulation of ANG gene expression. The local formation of Ang II may contribute to the induction of hypertrophy observed in proximal tubular cells in early diabetes.
Insulin therapy of patients with insulin-dependent diabetic mellitus (IDDM) delays the onset and slows the progression of nephropathy (15, 16). Studies in diabetic rats have shown that normalization of blood glucose by insulin reverses established glomerular hyperfiltration, renal hypertrophy and extracellular matrix protein synthesis (17, 18). The molecular mechanism(s) of the beneficial effects of insulin treatment, however, is not completely understood.
In the present studies, we investigated whether insulin might attenuate or inhibit the stimulatory effect of glucose on ANG gene expression in vitro and to study the possible underlying molecular mechanism(s) of action. Our studies showed that insulin inhibits the stimulatory effect of high levels of glucose (i.e. 25 mM) and phorbol 12-myristate 13-acetate (PMA) on the expression of the rat ANG gene in IRPTC. PD98059 (an inhibitor of MAP-kinase kinase, MEK) blocked the inhibitory effect of insulin on the ANG gene expression as well as on the phosphorylation of the MEK 1/2 and p44/42 MAP kinase. The addition of Wortmannin (an inhibitor of phosphatidylinositol-3-kinase (PI-3 kinase), however, did not reverse the inhibitory effect of insulin.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-[32P-ATP](3000 Ci/mol) and Na125I were
purchased from NEN Life Science Products (Boston, MA).
Oligonucleotides were synthesized by Life Technologies, Inc. (Burlington, Ontario, Canada). Restriction and modifying
enzymes were purchased from either Life Technologies, Inc., Roche Molecular Biochemicals (Dorval,
Québec, Canada) or Pharmacia Inc. (Baie
d’Urfé, Québec, Canada).
Phospho Plus MEK 1/2 antibody and Phospho Plus p44/42 MAP kinase kits were purchased from New England Biolabs, Inc. Ltd. (Mississauga, Ontario, Canada). The Phospho Plus MEK 1/2 and Phospho Plus p44/42 MAP kinase antibody kits are assays for rapid analysis of MEK 1/2 (Ser 217/221) and p44/42 MAP kinase (Thr 202/Tyr 204) phosphorylation status, respectively, that function in a mitogen-activated protein kinase cascade.
RIA for rat angiotensinogen
The RIA for rat ANG (RIA-rANG) was developed in our laboratory
(JSDC), and the procedure has been previously described in detail (6).
Purified rat plasma ANG (i.e. greater than 90% pure, as
analyzed by PAGE containing SDS-PAGE and iodinated rANG were used as
the hormone and tracer, respectively. This RIA is specific for intact
rat ANG (i.e. 62–65 kilodalton rANG) and has no
cross-reactivity with pituitary hormone preparations or other rat
plasma proteins (6). The lower limit of detection for the RIA is
approximately 2 ng of rANG. The intra and interassay coefficients of
variation were 9% (n = 10) and 14% (n = 10),
respectively.
Cell culture
IRPTC at passages 11 to 13 were used in the present studies. The
characteristics of IRPTC have been previously described (4). These
cells express the mRNA and protein of ANG, renin,
angiotensin-converting enzyme, and angiotensin-II receptor (4).
IRPTC were grown in 100 x 20 mm plastic Petri dishes (Life Technologies, Inc.) in normal glucose (i.e. 5 mM) DMEM (pH 7.45), supplemented with 10% FBS, 100 U/ml of penicillin and 100 µg/ml of streptomycin. The cells were grown in a humidified atmosphere in 95% air, 5% CO2 at 37 C. For subculturing, cells were trypsinized (0.05% trypsin and EDTA) and plated at 2.5 x 104 cells/cm2 in 100 x 20 mm Petri dishes.
Effect of glucose and insulin on the secretion of IR-rANG in
IRPTC
IRPTC were plated at a density of 1–2 x 105
cells/well in six-well plates and incubated overnight in normal glucose
(i.e. 5 mM) DMEM containing 10% FBS. Cell
growth was arrested by incubating the cells in serum-free medium with 5
mM glucose DMEM for 24 h. Various concentrations of
insulin (10-13 to 10-5 M) were
then added to a high (25 mM) glucose culture medium
containing 1% depleted FBS (dFBS) in the presence or absence of PMA
(10-7 M) and the cells were incubated for an
additional 24 h. At the end of the incubation period, media were
collected and stored at -20 C until assayed for IR-rANG. The depleted
FBS (i.e. depletion of endogenous steroid and thyroid
hormones) was prepared by incubation with 1% activated charcoal and
1% AG 1X 8 ion-exchange resin (Bio-Rad Laboratories, Inc., Richmond, CA) for 16 to 24 h at room temperature as
described by Samuels et al. (19).
To asses the specificity of the insulin effect, IGF-I or IGF-II at concentrations ranging between 1.3 x 10-11 to 1.3 x 10-8 M (final concentration) were added to the culture medium, and the cells were incubated for 24 h. To study whether the inhibitory effect of insulin is mediated via the PKC signal transduction pathway, IRPTC were pre-incubated for 24 h with 10-5 M PMA in a 25 mM glucose medium. Then, the cells were incubated with fresh 25 mM glucose medium containing 10-7 M PMA or various concentrations of insulin (10-11 to 10-5 M) for 24 h. To explore the involvement of the MAP kinase and PI-3 kinase pathways in mediating the effect of high levels of glucose or insulin on the secretion of the IR-rANG from IRPTC confluent cells were incubated for 24 h in media with 5 mM glucose, 25 mM glucose or 25 mM glucose and PMA (10-7 M) with or without insulin (10-7 M) plus various concentrations of PD98059 or Wortmannin. At the end of the incubation period, media were collected and stored at -20 C until assayed for IR-rANG.
Expression of ANG mRNA in IRPTC
To study the effect of glucose and insulin on the expression of
ANG mRNA in IRPTC, the cells were incubated in 5 mM
glucose, 25 mM glucose medium, 25 mM glucose
medium and insulin (10-7 M) in the absence or
presence of PD 98059 (10-5 M) for 24 h.
At the end of the incubation period, cells were collected and total RNA
was isolated using Trizol reagent (Life Technologies, Inc.
Burlington, Ontario, Canada) according to the protocol of the supplier.
The total RNA was used in an RT-PCR to quantitate the amount of ANG
mRNA expressed in IRPTC as described previously (14). Briefly, 1 µg
of total RNA was used to synthesize the complementary DNAs (cDNAs) by
employing the Super Script preamplification system, following the
protocol described by the supplier (Life Technologies, Inc.). Then, 2 µl of the cDNA reaction mixture was used to
amplify the rat ANG cDNA fragment using the PCR-core kit according to
the protocol of the supplier (Roche Molecular Biochemicals). The forward primer, 5' CCT CGC TCT CTG GAC TTA TC
3', and the reversed primer, 5' CAG ACA CTG AGG TGC TGT TG3',
corresponding to the nucleotide sequence of N+676 to N+695 and N+882 to
N+901 of the rat cDNA (20) were used in PCR. Furthermore, primers
specific for rat ß-actin (21) (forward and reversed primers, 5' ATG
CCA TCC TGC GTC TGG ACC TGG C3' AND 5' AGC ATT TGC GGT GCA CGA TGG AGG
G3' corresponding to nucleotide N+155 to N+179 of exon 3 and nucleotide
N+115 to N+139 of exon 5 of rat ß-actin) were used in another PCR
reaction as an internal control. The RT-PCR reaction mixture was then
separated on a 1.5% agarose gel and transferred onto a Gene-Screen
Plus nylon membrane (NEN Life Science Products).
Subsequently, 32P-labeled oligonucleotides corresponding to
the nucleotide N+775 to N+798 of the rat ANG cDNA (20) and nucleotide
of N+9 to N+35 of exon 4 of rat ß-actin (21) were used to hybridize
the membrane. Finally, the membrane was washed and exposed to
autoradiography. The relative densities of the PCR bands were
determined with a computerized laser densitometer.
Phosphorylation of MEK 1/2 and p44/42 MAP kinase in IRPTC
The effect of glucose and insulin on the activation of MAPK
signal transduction pathways in IRPTC was evaluated by the
phosphorylation of MEK 1/2 and p44/42 MAP kinase by employing Phospho
Plus MEK 1/2 and Phospho Plus p44/42 MAP kinase antibody kits,
respectively. Briefly, cells were plated at 5 x 104
cells/well in six-well plates in 5 mM glucose DMEM
containing 10% FBS, and were synchronized in 5 mM
glucose-medium for 24 h. Subsequently, the cells were incubated in
a 5 mM glucose, 25 mM glucose, 25
mM glucose and PD98059 (10-5 M)
for 15 min. Then insulin (10-7 M) was added
and the cells were incubated for another 10 min. Cells were lysed in
100 µl of lysis buffer (62.5 mM Tris-HCl, pH 6.8
containing 2% SDS (wt/vol), 10% glycerol, 50 mM DTT, and
0.1% bromophenol blue (wt/vol)) and harvested in
Eppendorf tubes. The cell lysates were sonicated for 2
sec, heated at 95 C for 5 min, and then centrifuged at 12,000 x
g for 2 min at 4 C. Small aliquots (20 µl) of the
supernatants were subjected to polyacrylamide gel (10%)
electrophoresis containing SDS-PAGE and then transferred onto a
nitrocellulose membrane (Hybond C Extra, Amersham Pharmacia Biotech, Oakville, Ontario, Canada). The membrane was then
blotted for the phosphorylated MEK 1/2 by employing the Phospho Plus
MEK 1/2 or Phospho Plus p44/42 MAP kinase antibody kit.
Statistical analysis
Three to four separate experiments per protocol were performed
and each treatment group was assayed in triplicate. The data were
analyzed with the Student’s t test or ANOVA analysis. A
probability level of P 
0.05 was regarded as
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) (P 0.005). The
addition of insulin to the culture medium abolished the high glucose
(25 mM)-stimulated secretion of the IR-rANG in IRPTC in a
dose-dependent manner (Fig. 1A) with a maximal effect observed at
10-7 to 10-5 M. This effective
dose of insulin, i.e. 10-7 M, was
therefore routinely used in all subsequent experiments. Unlike insulin,
IGF-I or IGF-II, at concentrations ranging from 1.3 x
10-11 to 1.3 x 10-8 M had
no significant effect on glucose-stimulated secretion of IR-rANG in
IRPTC (Fig. 1B).
|
0.005) in
IRPTC cultured in a normal (5 mM) glucose medium (Fig. 2A). This increase was similar to that
observed in IRPTC incubated in 25 mM glucose medium.
Addition of insulin to the culture medium inhibited the PMA stimulation
of secretion of the IR-rANG in IRPTC incubated in 5 mM
glucose medium (Fig. 2A). PMA (10-7 M)
augmented the stimulatory effect of a high level (25 mM) of
glucose to stimulate the secretion of the IR-rANG from IRPTC compared
with control cells cultured in 5 mM glucose
(P 0.005) (Fig. 2B). Insulin at 10-7 to
10-5 M completely inhibited the combined
effect of PMA and high glucose (25 mM) medium on the
secretion of the IR-rANG from IRPTC (Fig. 2B).
|
shows that the overnight
incubation of IRPTC in 25 mM glucose with a high
concentration of PMA (10-5 M) did not block
the inhibitory effect of insulin on the secretion of the IR-rANG. The
stimulatory effect of PMA (10-7 M), however,
was abolished. These studies demonstrate that the insulin inhibition of
the stimulatory effect of PMA on the secretion of the IR-rANG is
independent of PKC activation and may be mediated downstream in the PKC
signal transduction pathway or via another signal transduction
pathway.
|
shows that PD 98059
(10-11 to 10-7 M) had no effect
on the secretion of the IR-rANG from IRPTC stimulated by 25
mM glucose, wheras PD98059 at 10-5
M significantly (P 0.01) enhanced the
stimulatory effect of 25 mM glucose. Similarly, PD98059 at
10-7 to 10-6 M had no effect on
the secretion of the IR-rANG in IRPTC stimulated by 25 mM
glucose plus 10-7 M PMA (Fig. 4B). Again,
PD98059 at 10-5 and 10-4 M
significantly (P 0.005) enhanced the stimulatory
effect of 25 mM glucose and PMA (10-7
M). These studies indicate that the inhibition of MAP
kinase enhances the stimulatory effect of high levels of glucose on the
secretion of the ANG independent of the PKC pathway. On the other hand,
the inhibitory action of insulin on the secretion of the IR-rANG from
IRPTC cells was blocked by PD98059 in a dose-dependent manner (Fig. 5A) but was unaffected by Wortmannin
(10-8 to 10-4 M) (Fig. 5B). These
studies suggest that the inhibitory action of insulin is probably
mediated via the activation of MEK activity, but not via activation of
phosphatidylinositol-3-kinase.
|
|
shows that a high glucose
concentration (25 mM) stimulated the accumulation of the
ANG mRNA. ANG mRNA levels were 2.0-fold higher than those found in
control cells cultured in a medium containing 5 mM glucose
(P 0.05). Insulin (10-7 M)
completely inhibited the stimulatory effect of a high glucose (25
mM) on ANG mRNA in IRPTC. The addition of PD98059 blocked
the inhibitory effect of insulin.
|
shows that insulin
activated the phosphorylation of MEK 1/2 in IRPTC. The addition of
PD98059 inhibited the phosphorylation of MEK 1/2. Similarly, PD98059
also inhibited the phosphorylation of p44/42 MAP kinase stimulated by
insulin (Fig. 8). These studies
demonstrate that insulin is effective in activating the MAPK signal
transduction pathways in IRPTC.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
While several previous reports have described the expression of renal RAS genes in experimental diabetes mellitus (22, 23, 24), conflicting results have been obtained from different groups. Studies of Correra-Rother et al. (22) found that the renal renin protein and mRNA expression were not different between the diabetic and normal animals, but that renal and liver ANG mRNA levels were lower in the diabetic group. Kalinyak et al. (23) reported that there were no significant differences in the expression of renal renal and ANG mRNA in rats 2 weeks after the induction of diabetes compared with controls. In contrast, Anderson et al. (24) reported a small increase in renal renin and ANG gene expression in rats 6 to 8 weeks after induction of diabetes. While there is no clear rationalization for these, one obvious difference is the duration of diabetes in experimental rats used by these investigators.
The secretion of IR-rANG from IRPTC was increased by 1.5-fold in the
presence of a high glucose (25 mM) medium compared with a
normal glucose (5 mM) medium (Fig. 1A
). This level of
stimulation is similar to our previous studies, which showed that a
high level of glucose (25 mM) stimulated the expression of
the rat ANG gene by 1.5-fold in OK cells (13) and in IRPTC (14).
Studies by Chang and Perlman (25) have shown that insulin attenuated
the expression of the ANG mRNA in rat hepatoma cells in
vitro. More recently, Aubert et al. (26) also
demonstrated that insulin down-regulated ANG gene expression and
secretion in cultured adipose tissue. Consistent with these findings,
we have also observed that insulin inhibited the stimulatory effect of
glucose on the secretion of IR-rANG in a dose-dependent manner (Fig. 1A). These results, together with those of Chang and Perlman (25) and
Aubert et al. (26), suggest that insulin may down-regulate
ANG gene expression. We did not observe any significant inhibition of
the secretion of IR-rANG in IRPTC treated with various concentrations
of IGF-I or IGF-II (Fig. 1B), suggesting that the inhibitory action of
insulin on the secretion of IR-rANG in IRPTC is specific for insulin
and the insulin receptor.
The present studies show that PMA (10-7 M)
stimulated the secretion of IR-rANG in IRPTC incubated either in a
normal (5 mM) glucose medium (Fig. 2A) or in a high (25
mM) glucose medium (Fig. 2B), supporting the hypothesis
that the effect of high glucose levels on the expression of the ANG
gene is mediated via the PKC pathway (13, 14). Indeed, the involvement
of PKC in modulating the expression of ANG in IRPTC is confirmed by our
recent studies where it was reported that the stimulatory effect of a
high level (25 mM) of glucose on the expression of rat ANG
gene in OK cells (13) and IRPTC (14) is blocked in the presence of
inhibitors of PKC (i.e. staurosporine and H-7) and that PMA
(10-7 M) increased the ANG mRNA level in IRPTC
when incubated in 5 mM glucose medium (unpublished
results). It is interesting that insulin blocked the stimulatory effect
of PMA on the secretion of IR-rANG in IRPTC in a dose-depedent manner
(Fig. 2, A and B). Whereas overnight incubation of IRPTC with a high
dose of PMA (10-5 M) did not abolish the
inhibitory effect of insulin on the secretion of IR-rANG but it did
abolish the stimulatory effect of a lower dose of PMA
(10-7 M) (Fig. 3). These results are
consistent with the notion that the prolonged exposure to PMA will
down-regulate the PKC activity and protein expression levels (27).
While we do not understand the molecular mechanism(s) of the opposing
effect of PMA and insulin on the secretion of IR-rANG from IRPTC, our
observations raise the possibility that the inhibitory effect of
insulin on the secretion of the ANG may be mediated downstream of the
PKC signal transduction pathway or mediated via other signal
transduction pathways.
It is also interesting to note that PD 98059 [an inhibitor of MEK
(28)] at concentrations of 10-5 M or greater
enhanced the stimulatory effect of 25 mM glucose (Fig. 4A)
and 25 mM glucose plus PMA (Fig. 4B) on the secretion of
the rANG. These results indicate that the stimulatory effect of high
glucose (25 mM) and PMA on the secretion of ANG may be
enhanced by inhibition of the MEK signal transduction pathway. Indeed,
our results show that PD 98059 blocked the inhibitory effect of insulin
in a dose-dependent manner (Fig. 5A), whereas the addition of
Wortmannin [an inhibitor of phosphatidylinositol-3-kinase activity
(29)] had no effect (Fig. 5B). Furthermore, our preliminary studies
(Zhang, S. L., and J. S. D. Chan, unpublished results) showed
that PMA (10-7 M) did not stimulate the
phosphorylation of p44/42 MAP kinase in IRPTC. These data are
consistent with the notion that the inhibitory effect of insulin is
mediated, at least in part, via the MEK pathway and independent of PKC
signal transduction pathway.
The effects of glucose and insulin on ANG gene expression appears to
occur at the mRNA level. Exposure of IRPTC to a high glucose
concentration (25 mM) significantly (P
0.05) stimulated the expression of ANG mRNA (i.e. an
increase of 2-fold) compared with expression in control cells (cultured
in 5 mM glucose medium) (Fig. 6). Insulin
(10-7 M) completely blocked the stimulatory
effect of 25 mM glucose. PD98059 reversed the inhibitory
effect of insulin. At present, it is uncertain whether insulin
decreases ANG mRNA levels at the transcriptional level or affects the
stability of the ANG mRNA in IRPTC. Studies are ongoing in our
laboratory to investigate these possibilities.
At present, we do not understand the exact molecular mechanism(s) of high glucose levels on the expression of the ANG gene in IRPTC. One possibility may be that high glucose levels may stimulate de novo synthesis of diacylglycerol (DAG) from metabolized glucose via the polyol pathway as suggested by Tilton et al. (30), leading to an increase PKC activity. Indeed, our recent studies showed that high levels of glucose increase the cellular levels of DAG and PKC activity in IRPTC (14). Once PKC is activated, it may phosphorylate the 43-kDa cAMP-responsive element binding protein (CREB) or CREB-like nuclear protein(s) because 43 kDa CREB contains the site of phosphorylation by PKC (31). Moreover, recent studies by Kreisberg et al. (32) have shown that PMA and high glucose levels stimulate the phosphorylation of 43 kDa CREB. Phosphorylated CREB then binds to the cAMP-responsive element (CRE) of the rat ANG gene (TGACGTAC, nucleotides N-795 to N-788) (33). Subsequently, the bound CREB stimulates the expression of the rat ANG gene. This possibility is supported by our recent studies, which demonstrated that the transient transfection of 43 kDa CREB into OK cells stimulates the expression of rat ANG gene promoter activity (34) and that ANG-CRE binds with the 43 kDa-CREB (35).
Similarly, we do not understand the precise molecular mechanism(s) of
action of the inhibitory effect of insulin on the expression of ANG
gene in IRPTC. One possibility might be that insulin activates the MAP
kinase signal transduction pathway as shown in Figs. 7 and 8 and
induces the phosphorylation or expression of certain protein(s). The
insulin-induced protein(s) then suppress(es) the expression of the ANG
gene via a yet undefined pathway. Indeed, recent studies have shown
that insulin induces c-Fos expression via MAP kinase but not PI-3
kinase in 32 D mouse myeloid progenitor cells (36) and in vascular
smooth muscle cells (37), suggesting that MAP kinase signal
transduction pathway is important for insulin action. Whether insulin
will also induce the expression of c-Fos gene in IRPTC, remains,
however, to be studied. Alternatively, the inhibitory effect of insulin
may be mediated, at least in part, via an insulin-responsive element
(IRE) in the 5'-flanking region of the ANG gene. Several studies have
reported that insulin stimulates and/or inhibits the gene expression
via the putative IRE in the 5'-flanking region of various genes
(38, 39, 40). To our best knowledge, the IRE in the rat ANG gene has not
yet been identified. Studies along these lines, however, are underway
in our laboratory.
It is unlikely that the inhibitory action of insulin on the expression
of the ANG gene is mediated via the PI-3 kinase signal transduction
pathway, because Wortmannin failed to block the inhibitory effect of
insulin on the secretion of the ANG from IRPTC (Fig. 5).
In summary, our studies demonstrate that the exposure of IRPTC to 25 mM glucose directly stimulates the expression of the rat ANG gene in IRPTC. This stimulatory effect of high glucose was blocked by insulin via the MAPK kinase signal transduction pathway. These findings raise the possibility that the expression of the renal ANG gene may be stimulated by hyperglycemic states in vivo. Consequently, the increased local formation of renal Ang II may contribute to renal remodeling (i.e. renal hypertrophy observed in early diabetes). Insulin therapy may therefore attenuate this event by inhibiting the activation of local renal RAS. Furthermore, chronic treatment with inhibitors of angiotensin-converting enzyme (ACE) and AT1-angiotensin II (Ang II) receptor have also been shown to delay the onset and the development of nephropathy in patients with insulin-dependent diabetic mellitus (41, 42, 43, 44, 45). These studies raise the possibility that a combination of both insulin and ACE-inhibitor(s) or AT1-receptor antagonists may be a more effective therapy than the treatment with either insulin or ACE-inhibitor alone. Therefore, this therapeutic approach should be explored in experimental animals and in patients with diabetic mellitus.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received February 11, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 C.-C. Wei, S.-L. Zhang, Y.-W. Chen, D.-F. Guo, J. R. Ingelfinger, K. Bomsztyk, and J. S. D. Chan Heterogeneous Nuclear Ribonucleoprotein K Modulates Angiotensinogen Gene Expression in Kidney Cells J. Biol. Chem., September 1, 2006; 281(35): 25344 - 25355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wei, D.-F. Guo, S.-L. Zhang, J. R. Ingelfinger, and J. S.D. Chan Heterogenous Nuclear Ribonucleoprotein F Modulates Angiotensinogen Gene Expression in Rat Kidney Proximal Tubular Cells J. Am. Soc. Nephrol., March 1, 2005; 16(3): 616 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-J. Hsieh, P. Fustier, C.-C. Wei, S.-L. Zhang, J. G Filep, S.-S. Tang, J. R Ingelfinger, I G. Fantus, P. Hamet, and J. S D Chan Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells J. Endocrinol., December 1, 2004; 183(3): 535 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-J. Hsieh, P. Fustier, S.-L. Zhang, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, I. G. Fantus, P. Hamet, and J. S. D. Chan High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells Endocrinology, October 1, 2003; 144(10): 4338 - 4349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Banday, M. Asghar, T. Hussain, and M. F. Lokhandwala Dopamine-Mediated Inhibition of Renal Na,K-ATPase Is Reduced by Insulin Hypertension, June 1, 2003; 41(6): 1353 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-L. Zhang, X. Chen, C.-C. Wei, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, and J. S. D. Chan Insulin Inhibits Dexamethasone Effect on Angiotensinogen Gene Expression and Induction of Hypertrophy in Rat Kidney Proximal Tubular Cells in High Glucose Endocrinology, December 1, 2002; 143(12): 4627 - 4635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, S.-L. Zhang, L. Pang, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, and J. S. D. Chan Characterization of a Putative Insulin-Responsive Element and Its Binding Protein(s) in Rat Angiotensinogen Gene Promoter: Regulation by Glucose and Insulin Endocrinology, June 1, 2001; 142(6): 2577 - 2585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-L. Zhang, S.-S. Tang, X. Chen, J. G. Filep, J. R. Ingelfinger, and J. S. D. Chan High Levels of Glucose Stimulate Angiotensinogen Gene Expression Via the P38 Mitogen-Activated Protein Kinase Pathway in Rat Kidney Proximal Tubular Cells Endocrinology, December 1, 2000; 141(12): 4637 - 4646. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
