Hypertension. 1998;31:885-889
(Hypertension. 1998;31:885-889.)
© 1998 American Heart Association, Inc.
Gene Expression of 11ß-Hydroxysteroid Dehydrogenase Type 1 and Type 2 in the Kidneys of Insulin-Dependent Diabetic Rats
Yan-Jun Liu;
Yuichi Nakagawa;
; Takehiko Ohzeki
From the Department of Pediatrics, Hamamatsu University School of
Medicine, Hamamatsu, Japan.
Correspondence to Yan-Jun Liu, Department of Pediatrics, Hamamatsu University School of Medicine, 3600 Handa-Cho, Hamamatsu 431–31, Japan.
 |
Abstract
|
|---|
Abstract—The presence of
11ß-hydroxysteroid dehydrogenase (11ß-HSD) activity in the kidney
has been suggested to be important in the regulation of
glucocorticoid-induced disorders of electrolyte balance and the control
of blood pressure. To assess the possible effect of 11ß-HSD isoforms
in diabetes-related hypertension, we measured the mean systolic
blood pressure and the 11ß-HSD activity and mRNA levels for both
11ß-HSD1 and 11ß-HSD2 in the kidney of streptozotocin
(STZ)-diabetic female rats. Three weeks after injection of STZ (65
mg/kg), the mean systolic blood pressure of diabetic rats was
elevated 13.6% above that of normal rats (P<.01). The
renal 11ß-HSD2 activity and level of mRNA expression were
significantly decreased in diabetic rats (P<.01).
However, the treatment of rats with STZ did not decrease the levels of
renal 11ß-HSD1 activity and mRNA expression in diabetic rats. Insulin
administered subcutaneously to diabetic rats for 2 weeks completely
reversed the decrease in renal 11ß-HSD2 activity and gene expression
and prevented the elevation in blood pressure in the diabetic rat.
These results indicate that alteration of renal 11ß-HSD2 activity and
gene expression may be primarily responsible for the changes in blood
pressure of STZ-diabetic rats after early treatment with insulin.
Key Words: 11ß-hydroxysteroid dehydrogenase • streptozotocin • diabetes mellitus • kidney • blood pressure • insulin
|
Introduction
|
|---|
The MR is known to
have a similar in vitro affinity for physiological
glucocorticoid corticosterone and cortisol and mineralocorticoid
aldosterone.1 2 In vivo,
corticosterone or cortisol, which circulates at far higher levels than
aldosterone, cannot occupy the MR because it is oxidized to
11-dehydrocorticosterone or cortisone by
two different renal 11ß-HSD enzymes,3 4 a
low-affinity NADP+-dependent dehydrogenase
(11ß-HSD1) and a high-affinity NAD+-dependent
dehydrogenase (11ß-HSD2).5 6 Impairment of
11ß-HSD activity in rats and humans has been demonstrated to produce
a glucocorticoid (corticosterone and cortisol)-dependent
mineralocorticoid excess and hypertension.7 8 9 In
particular, 11ß-HSD2 is found in the distal nephron of the kidney,
the site of mineralococorticoid action,6 and it
has been shown to be the principal function isoform protecting renal MR
from the effects of endogenous glucocorticoids and
conferring aldosterone selectivity on MR. Several major
studies have also demonstrated inhibition of renal 11ß-HSD2 activity
by exogenous and endogenous
inhibitors,10 11 12 thus preventing
inactivation of corticosterone in the distal tubules of the kidney,
allowing corticosterone to access renal MR and causing significant
Na+ retention and the development of
hypertension.
Hypertension is frequently seen in IDDM.13 14 In
the STZ-induced diabetic rat, elevated blood pressure is observed
within 1 to 2 weeks of STZ injection, and this hypertension can be
prevented by early treatment with insulin.15 16
However, the mechanism responsible for this abnormal elevation in blood
pressure is not well understood. Whether diabetes-induced hypertension
is related to diabetes-associated alterations in renal 11ß-HSD1 and
11ß-HSD2 remains unclear. Therefore, we measured the mean
systolic blood pressure and the levels of isoform enzyme
activity and mRNA expression for both 11ß-HSD1 and 11ß-HSD2 in the
kidney of STZ-induced diabetic rats after treatment with insulin.
|
Methods
|
|---|
Experimental Animals
Female Sprague-Dawley rats (8 weeks of age) were obtained from
Charles River Laboratories (Shizuoka, Japan). All rats were maintained
on standard chow and drank tap water ad libitum. Diabetes was induced
by intravenous injection of STZ (65 mg/kg body wt) (Wako
Pure Chemical Industries) in 0.01 mol/L citrate buffer, pH 4.0. Control
rats received an equal volume of citrate buffer. After 3 days, diabetes
was confirmed by measurement of blood glucose concentrations and
insulin levels. Diabetic animals were randomly separated into untreated
and insulin-treated groups. One week after the administration of STZ,
diabetic rats were given a subcutaneous injection of insulin (Sigma
Chemical Co) at a dose of 12.5 IU/kg body wt twice a day for 2 weeks.
The doses of STZ and insulin and the treatment regimen were similar to
those previously used by other
investigators.17 18 All animals were
anesthetized and killed 3 weeks after administration of STZ or
vehicle.
Measurement of Blood Glucose, Insulin, and Blood Pressure
Plasma glucose and insulin samples were obtained at the time of
death. Plasma glucose concentration was measured using a glucose
oxidase system (Boehringer-Mannheim). Serum insulin was
measured by double-antibody radioimmunoassay, using rat insulin as a
standard. Blood pressure was measured by the tail-cuff
method.19 Blood pressure was expressed as the
mean of at least four measurements.
Enzyme Activity Assay
The enzyme activities of the 11ß-HSD1 and 11ß-HSD2 isoforms
were determined by measuring the conversion of corticosterone (B) to
11-dehydrocorticosterone (A), as previously
reported.11 20 21 22 Briefly, kidney tissues were
homogenized in Krebs-Ringer buffer solution at 4°C in a
Dounce tissue grinder. Tissue homogenates were
centrifuged at 1000g for 10 minutes at 4°C to
sediment large tissue fragments, the protein concentrations of the
supernatant were measured in a homogenate dilution by the
method of Bradford (Bio-Rad protein assay kit), and the
homogenate supernatant was diluted appropriately to yield a
consistent protein concentration. Kidney
homogenates (200 to 250 µL) were incubated with 100
nmol/L [3H]B (specific activity, 90 Ci/mmol;
New England Nuclear Corp) and 200 µmol/L
NAD+ (for 11ß-HSD2 activity in the kidney) or
2 µmol/L [3H]B and 3.4 mmol/L
NADP+ (for 11ß-HSD1 activity in kidney), at
37°C for 12 minutes in a shaking bath. Preliminary studies
established that the protein concentration in each reaction was
adjusted to ensure the linearity of product formation over the 12
minutes of incubation. Steroids were extracted with ethyl acetate and
separated by thin-layer chromatography in a
chloroform-ethanol (9:1) system. The conversion of
[3H]B to [3H]A was
measured from the radioactivity of each fraction.
RNA Preparation and Probe Hybridization
Total RNA was isolated from kidney tissues by modified acid
guanidinium thiocyanate phenol chloroform methods as described
previously.21 For Northern blotting, 20 µg of
total RNA per lane were electrophoresed and transferred to a nylon
membrane (Hybond-N+, Amersham) by capillary
transfer. To assist in the quantification of the mRNA levels, type I
11ß-HSD1 (1265 bp) cDNA, and type II 11ß-HSD2 (1864 bp) cDNA
(kindly provided by Drs White23 and
Gomez-Sanchez24 ) were labeled with
[32 P]ATP (Amersham International plc; specific
activity, 6000 Ci/mmol) using nick translation (Nick Translation
System, BRL Life Technologies, Inc). For densitometric measurements,
autoradiographic signals were standardized to signals
determined from 18S rRNA in each preparation to control for the amount
of RNA loaded per lane.
Data Analysis
Results are given as the mean±SEM for the indicated number of
rats. Comparisons among the different experimental groups were carried
out by unpaired Student's t test and ANOVA. Values of
P<.05 were considered statistically significant.
|
Results
|
|---|
The Table
shows changes in the blood glucose, insulin,
and blood pressure during the 3 weeks after intravenous
injection with STZ. The blood glucose levels of untreated STZ-diabetic
female rats were significantly increased compared with age-matched
nondiabetic female rats (P<.001). The treatment of female
rats with STZ resulted in a marked reduction in the levels of serum
insulin compared with nondiabetic female rats of the same age
(P<.01). Three weeks after STZ treatment, the mean
systolic blood pressure of diabetic female rats was
147±5.0 mm Hg, 13.6% higher than that of normal female rats
(127±3.85 mm Hg) (P<.01). Administration of insulin
to STZ-induced diabetic rats for 2 weeks reversed the increase in the
blood glucose concentrations of diabetic rats. STZ-diabetic rats
treated with insulin maintained the blood pressure of control
nondiabetic rats, as shown in the Table.
View this table:
[in this window]
[in a new window]
|
Table 1. Blood Glucose, Insulin, and Blood Pressure in Normal and
Diabetic Rats With or Without Insulin Treatment
|
|
In STZ-diabetic female rats, renal 11ß-HSD2 activity was significant
lower (26.10±1.18 versus 15.10±0.7%, respectively) than that of
normal female rats (P<.005) (Fig 1). Subcutaneous administration of
insulin to STZ-diabetic female rats for 2 weeks resulted in a
significant rise in the level of renal 11ß-HSD2 activity compared
with untreated diabetic rats (P<.005). However, there were
no significant differences in the activity level of this enzyme between
insulin-treated diabetic rats and normal rats of the same age (Fig 1).
Fig 2 shows the results of Northern blot
analysis of 11ß-HSD2 mRNA expressions in the kidneys of
diabetes and normal rats. The levels of 11ß-HSD2 mRNA in the kidneys
of diabetic rats were significantly lower than in normal rats of the
same age (P<.01) (Fig 2). Similarly, when insulin was
administered by subcutaneous injection to diabetic rats, the levels of
renal 11ß-HSD2 mRNA expression of diabetic rats were restored to that
of normal rats (Fig 2).
View larger version (16K):
[in this window]
[in a new window]
|
Figure 1. 11ß-HSD2 activity in kidneys from normal female
rats (NORMAL, n=7), diabetic female rats (DIAB, n=6), and diabetic
female rats treated with insulin (DIAB+I, n=6). The enzyme activity is
expressed as percentage conversion of [3H]B to
[3H]A. Values are mean±SEM. *P<.005
compared with normal rats. **P<.005 compared with
untreated diabetic rats.
|
|
View larger version (52K):
[in this window]
[in a new window]
|
Figure 2. Northern blot hybridization of 11ß-HSD2 cDNA and
[18S]rDNA probes shows mRNA expression and quantification
of 11ß-HSD2 mRNA levels in kidneys of normal female rats
(NORMAL), diabetic female rats (DIAB), and diabetic female rats treated
with insulin (DIAB+I). Values are expressed as mean±SEM of the ratio
of 11ß-HSD2/[18S]mRNA levels. *P<.01
compared with normal female rats. **P<.01 compared with
untreated diabetic rats.
|
|
In contrast, the treatment of rats with STZ increased the level of
renal 11ß-HSD1 activity (P<.01) (Fig 3); this increase in enzyme activity was
paralleled by significantly increased levels of renal 11ß-HSD1
mRNA expression in STZ-induced diabetic rats compared with normal rats
(P<.05) (Figs 3 and 4).
Treatment of diabetic rats with insulin reversed the increase in renal
11ß-HSD1 activity of STZ-diabetic rats to levels equivalent to those
found in normal male rats. In parallel, administration of insulin to
STZ-diabetic rats significantly decreased renal 11ß-HSD1 mRNA levels
to the normal range (Figs 3 and 4).
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3. 11ß-HSD1 activity in kidneys of normal female
rats (NORMAL, n=7), diabetic female rats (DIAB, n=6), and diabetic
female rats treated with insulin (DIAB+I, n=6). Enzyme activity is
expressed as percentage conversion of [3H]B to
[3H]A. Values are mean±SEM. *P<.01
compared with normal rats. **P<.01 compared with
untreated diabetic rats.
|
|
View larger version (59K):
[in this window]
[in a new window]
|
Figure 4. Northern blot hybridization of 11ß-HSD1 cDNA and
[18S]rDNA probes shows mRNA expression and quantification
of 11ß-HSD1 mRNA expression in kidneys of normal female rats
(NORMAL), diabetic female rats (DIAB), and diabetic female rats treated
with insulin (DIAB+I). Values are expressed as mean±SEM of the ratio
of 11ß-HSD1/[18S]mRNA levels. *P<.05
compared with normal rats. **P<.05 compared with
untreated diabetic rats.
|
|
|
Discussion
|
|---|
11ß-HSD2 has been demonstrated to be the major isoform of this
enzyme in animal and human kidney. The recombinant enzyme only shows
dehydrogenase activity and has a very high affinity for
glucocorticoids. Importantly, localization studies have established
that the presence of 11ß-HSD2 in the distal tubule of kidney was
colocalized with MR.25 26 Moreover, the primary
function of 11ß-HSD2 has been documented to provide a protective
mechanism that prevents glucocorticoids from binding to MRs and thereby
playing a key role in the regulation of glucocorticoid-induced
Na+ retention and blood pressure. Defective
11ß-HSD2 activity or inhibition of the enzyme is associated with
severe hypertension in the syndromes of AME or carbenoxolone,
respectively.9 10 Other lines of evidence have
shown that exogenous and endogenous substances such as
glycyrrhetinic acid, carbenoxolone, and 11
-hydroxyprogesterone,
which potently inhibit 11ß-HSD2 activities, result in
glucocorticoid-dependent mineralocorticoid excess, causing
Na+ retention and hypertension in rats and
children.7 10 11 12 Furthermore, the
hypertensinogenic effects of these substances were inhibited by the
specific MR antagonist RU
28318.10 11 27 These studies indicate that the
inhibition of 11ß-HSD2 activity can cause hypertension through the
activation of MRs.
More recent studies have found that the hypertension is strongly
correlated with a deficiency in the kidney-specific type II 11ß-HSD
(11ß-HSD2) by the demonstration of mutations in the 11ß-HSD2 gene
of AME proteins.7 8 9 Our data indicate that
diabetic rats had markedly decreased renal 11ß-HSD2 enzyme activity
and mRNA expression that was associated with hypertension. Inhibition
of this enzyme activity and gene expression in diabetes may thus allow
corticosterone to access renal MRs, causing inappropriate
Na+ retention and blood pressure elevation in
STZ-diabetic rats.
It is generally thought that the hypertensive action of STZ-induced
diabetes may be secondary to the loss of insulin secretion, a
consequence of damage to pancreatic
ß-cells,28 29 and that the diabetes-induced
elevation in blood pressure can be normalized by early treatment with
insulin in the STZ-induced diabetic rat.16 17 The
role of insulin in controlling blood pressure elevation in diabetes is
thought to be due to its ability to regulate renal
Na+ balance, Na+-
K+-ATPase activity, renin-angiotensin
axis, renal function, vasopressor hormones, sympathetic nervous system
activity, intracellular cation transport, and glucose
metabolism,17 30 31 32 33 all of which are
associated with the pathogenesis of hypertension in the STZ-diabetic
rat. Moreover, diabetes-induced hyperglycemia may elevate levels of
insulin-counteracting hormones, such as epinephrine,
norepinephrine, glucagon and cortisol, or
corticosterone,34 35 36 37 38 which can contribute to the
development of diabetes-related hypertension by impairing carbohydrate
metabolism. In the present study, our results indicate
that diabetes reduced the concentration of serum insulin and elevated
blood pressure, with simultaneous impairment of renal
11ß-HSD2 activity. Moreover, treatment of STZ-diabetic rats with
insulin restored the decreased levels of renal 11ß-HSD2 activity and
could fully prevent hypertension. Therefore, we conclude that the
decreased renal 11ß-HSD2 activity and mRNA expression play important
roles in the hypertension observed in STZ-diabetic rats, and the
effects of insulin on blood pressure may be associated with renal
11ß-HSD2 enzyme in IDDM during early-phase insulin treatment.
Although diabetes markedly elevated blood pressure, there was no
inhibition of either renal 11ß-HSD1 activity or mRNA levels in
STZ-diabetic rats. Similarly, 11ß-HSD1 gene expression is normal in
congenital AME,39 and a mutation in the
11ß-HSD2 gene can explain this syndrome.9 There
was also no impairment of 11ß-HSD1 activity or gene expression in the
hypertensive Bianchi-Milan rat.20 Moreover, the
11ß-HSD1 enzyme does not colocalize with MR in kidney. Other studies
have also demonstrated that low affinity and lack of colocalization
with MR rule out a role for the 11ß-HSD1 enzyme in the protection of
glucocorticoid occupation of the MR, and that the renal 11ß-HSD2 is
the protective enzyme that is most likely to confer mineralocorticoid
specificity on the MR-mediated mechanism that controls blood pressure,
in keeping with our results. The increases in renal 11ß-HSD1 activity
and mRNA expression of diabetic rats were consistent with
earlier reports that observed the inhibitory effects of
insulin on 11ß-HSD1 in humans and
rats.40 41
In addition, diabetes studies have demonstrated that the hyperglycemia
induces an increase in intracellular NADP+-NADH
and a reduction in the NAD+-NADH ratio as a
result of increased reduction of glucose to sorbitol and oxidation of
sorbitol to fructose by means of the sorbitol
pathway.42 43 The present study showed that
diabetes increased renal 11ß-HSD1 activity but decreased renal
11ß-HSD2 activity in STZ-diabetic rats. The data might also support
the concept that a higher NADP+-NADH ratio
induces the dehydrogenase activity of 11ß-HSD1, but it seems
improbable that a lower NAD+-NADH level
stimulates 11ß-HSD2 activity.
|
Selected Abbreviations and Acronyms
|
|---|
| A |
= |
11-dehydrocorticosterone |
| AME |
= |
apparent mineralocorticoid excess |
| B |
= |
corticosterone |
| 11ß-HSD |
= |
11ß-hydroxysteroid dehydrogenase |
| IDDM |
= |
insulin-dependent diabetes mellitus |
| MR |
= |
mineralocorticoid receptor |
| STZ |
= |
streptozotocin |
|
|
Acknowledgments
|
|---|
This work was supported in part by a grant from the Research
Committee on Disorders of Adrenal Hormones under the auspices of the
Ministry of Health and Welfare of Japan.
Received July 7, 1997;
first decision July 30, 1997;
accepted October 20, 1997.
|
References
|
|---|
-
Arriza JL, Weinberger C, Cerelli G, Glaser TM,
Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid
receptor complementary DNA: structural and functional kinship with the
glucocorticoid receptor. Science. 1987;237:268–275.[Abstract/Free Full Text]
-
Krozowski ZS, Funder JW. Renal mineralocorticoid
receptors and hippocampal corticosterone binding species have identical
intrinsic steroid specificity. Proc Natl Acad Sci U S A. 1983;80:6056–6060.[Abstract/Free Full Text]
-
Funder JW, Pearce PT, Smith R, Smith AI.
Mineralocorticoid action: target tissue specificity is enzyme, not
receptor, mediated. Science. 1988;242:583–585.[Abstract/Free Full Text]
-
Edwards CRW, Stewart PM, Burt D, Brett L, McIntyre MA,
Sutanto WS, de Kloet ER, Monder C. Localisation of
11ß-hydroxysteroid dehydrogenase-tissue-specific protector of
the mineralococorticoid receptor. Lancet. 1988;2:986–989.[Medline]
[Order article via Infotrieve]
-
Monder C, White PC. 11ß-hydroxysteroid
dehydrogenase. Vitam Horm. 1993;47:187–271.[Medline]
[Order article via Infotrieve]
-
Rusvai E, Naray-Fejes-Toth A. A new isoforms of
11ß-hydroxysteroid dehydrogenase in aldosterone
target cells. J Biol Chem. 1993;268:10717–10720.[Abstract/Free Full Text]
-
Penning TM. Molecular endocrinology of hydroxysteroid
dehydrogenases. Endocrin Rev. 1997;18:282–305.
-
Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC.
Human hypertension caused by mutations in the kidney isozyme of
11ß-hydroxysteroid dehydrogenase. Nat Genet. 1995;10:394–399.[Medline]
[Order article via Infotrieve]
-
White PC, Mune T, Rogerson FM, Kayes KM, Agarwal AK.
11ß-Hydroxysteroid dehydrogenase and its role in the syndrome of
apparent mineralococorticoid excess. Pediatr Res. 1997;41:25–29.[Medline]
[Order article via Infotrieve]
-
Lo YH, Sheff MF, Latif SA, Ribeiro C, Silver H, Brem
AS, Morris DJ. Kidney 11ß-HSD2 is inhibited by glyrrhetinic
acid-like factors in human urine. Hypertension. 1997;29(pt
2):500–505.
-
Souness GW, Latif SA, Laurenzo JL, Morris DJ.
11- and 11ß-Hydroxyprogesterone, potent
inhibitors of 11ß-hydroxysteroid dehydrogenase (isoforms
1 and 2), confer marked mineralococorticoid activity on corticosterone
in the ADX rat. Endocrinology. 1995;136:1809–1812.[Abstract]
-
Souness GW, Morris DJ. 11- and
11ß-Hydroxyprogesterone, potent inhibitors of
11ß-hydroxysteroid dehydrogenase, possess hypertensinogenic activity
in rat. Hypertension. 1996;27(pt 1):421–425.
-
Weidman P, Mogensen CE, Ritz E. Hypertension associated
with diabetes mellitus. Hypertension. 1985;7(suppl
II):II-1–II-2.
-
Epstein M, Sowers JR. Diabetes mellitus and
hypertension. Hypertension. 1992;19:403–418.[Abstract/Free Full Text]
-
Chen S, Yuan C, Haddy FJ, Clough D, Pamnani MB. Effect
of insulin on the development of streptozotocin-induced diabetes
hypertension in rat. J Am Soc Nephrol. 1992;3:756A.
Abstract.
-
Sasaki S, Bunag RD. Insulin reverses hypertension and
hypothalamic depression in streptozotocin diabetic rats.
Hypertension. 1983;5:34–40.[Abstract/Free Full Text]
-
Ramos OL. Diabetes mellitus and hypertension: state of
the art lecture. Hypertension. 1988;11(2 pt 2):114–118.
-
Favreau LV, Schenkman JB. Composition changes in
hepatic microsomal cytochrome P-450 during onset of
streptozocin-induced diabetes and during insulin treatment.
Diabetes. 1988;37:577–584.[Abstract]
-
Pfeffer JM, Pfeffer MA, Frohlich ED. Validity of an
indirect tail-cuff method for determining systolic
arterial pressure in unanaesthetized normotensive and
spontaneously hypertensive rats. J Lab Clin Med. 1971;78:957–962.[Medline]
[Order article via Infotrieve]
-
Stewart PM, Whorwood CB, Vatentino R, Burt D, Sheppard
MC, Edwards CRW. 11-Beta-hydroxysteroid dehydrogenase activity and gene
expression in the hypertensive Bianchi-Milan rat. J
Hypertens. 1993;11:349–354.[Medline]
[Order article via Infotrieve]
-
Liu YJ, Nakagawa Y, Toya K, Ozeki T. Sex-specific
effects of growth hormone on hepatic 11ß-hydroxysteroid dehydrogenase
activity and gene expression in hypothyroid rats. Life Sci. 1997;61:325–334.[Medline]
[Order article via Infotrieve]
-
Waddell BJ, Bendiktsson R, Seckl J.
11ß-Hydroxysteroid dehydrogenase type 2 in the rat corpus
luteum: induction of messenger ribonucleic acid expression and
bioactivity coincident with luteal regression.
Endocrinology. 1996;137:5386–5391.[Abstract]
-
Agarwal AK, Monder C, Eckstein B, White PC. Cloning and
expression of rat cDNA encoding corticosteroid
11ß-dehydrogenase. J Biol Chem. 1989;264:18939–18943.[Abstract/Free Full Text]
-
Zhou MY, Gomez-Sanchez EP, Cox DL, Cosby D,
Gomez-Sanchez CE. Cloning, expression, and tissue distribution of the
rat nicotinamide adenine dinucleotide-dependent
11ß-hydroxysteroid dehydrogenase. Endocrinology. 1995;136:3729–3734.[Abstract]
-
Naray-Fejes-Toth A, Watlington CO, Fejes-Toth G.
11ß-Hydroxysteroid dehydrogenase activity in the renal target
cells of aldosterone. Endocrinology. 1991;129:17–21.[Abstract]
-
Kenouch S, Alfaidy N, Bonvalet JP, Farman N. Expression
of 11ß-OHSD along the nephron of mammals and human.
Steroids. 1994;59:100–104.[Medline]
[Order article via Infotrieve]
-
Gomez-Sanchez EP, Gomez-Sanchez CE. Central
hypertensinogenic effects of glycyrrhizic acid and carbenoxalone.
Am J Physiol. 1992;263:E1125–E1130.
-
Kawashima H, Igarashi T, Nakajima Y, Akiyama Y, Usuki
K, Ohtake S. Chronic hypertension induced by streptozotocin in rats.
Naunyn Schmiedebergs Arch Pharmacol. 1978;305:123–126.[Medline]
[Order article via Infotrieve]
-
Junod A, Lambert AE, Orci L, Pictet R, Gonet AE, Renold
AE. Studies of the diabetogenic action of streptozotocin. Proc
Soc Exp Biol Med. 1967;126:201–205.[Medline]
[Order article via Infotrieve]
-
DeFronzo RA. The effect of insulin on renal sodium
metabolism. Diabetologia. 1981;21:165–171.[Medline]
[Order article via Infotrieve]
-
Chen S, Yuan CM, Haddy FJ, Pamnani MB. Effect of
administration of insulin on streptozotocin-induced diabetic
hypertension in rat. Hypertension. 1994;23(pt 2):1046–1050.
-
Ferrari P, Weidmann P. Insulin, insulin sensitivity and
hypertension. J Hypertens. 1990;8:491–500.[Medline]
[Order article via Infotrieve]
-
O'Shaughnessy IM, Myers TJ, Stepniakowski K, Nazzaro
P, Kelly TM, Hoffmann RG, Egan BM, Kissebah AH. Glucose
metabolism in abdominally obese hypertensive and
normotensive subjects. Hypertension. 1995;26:186–192.[Abstract/Free Full Text]
-
Bratusch-Marrain PR. Insulin-counteracting hormones:
their impact on glucose metabolism.
Diabetologia. 1983;24:74–79.[Medline]
[Order article via Infotrieve]
-
Waldhausl W, Kleinberger G, Korn A, Dudczak R,
Bratusch-Marrain P, Nowotny P. Severe hyperglycemia: effects of
rehydration on endocrine derangements and blood glucose concentration.
Diabetes. 1979;28:577–584.[Medline]
[Order article via Infotrieve]
-
Shikama H, Ui M. Attenuation of
epinephrine-induced increase in liver cyclic AMP by
endogenous insulin in vivo. Biochim Biophys
Acta. 1976;444:461–471.[Medline]
[Order article via Infotrieve]
-
Weir GC, Knowlton SD, Atkins RF, Mckennan KX, Martin
DB. Glucagon secretion from the perfused pancreas of
streptozotocin-treated rats. Diabetes. 1976;25:275–282.[Abstract]
-
De Nicola AF, Fridman O, Del Castillo EJ, Foglia VG.
Abnormal regulation of adrenal function in rats with streptozotocin
diabetes. Horm Metab Res. 1977;9:469–473.[Medline]
[Order article via Infotrieve]
-
Nikkila H, Tannin GM, New MI, Taylor NF, Kalaitzoglou
G, Monder C, White PC. Defects in the HSD11 gene encoding
11ß-hydroxysteroid dehydrogenase are not found in patients with
apparent mineralocorticoid excess or 11-oxoreductase deficiency.
J Clin Endocrinol Metab. 1993;77:687–691.[Abstract]
-
Liu YJ, Nakagawa Y, Nasuda K, Saegusa H, Igarashi Y.
Effect of growth hormone, insulin and dexamethasone on
11ß-hydroxysteroid dehydrogenase activity on a primary culture of rat
hepatocytes. Life Sci. 1996;59:227–234.[Medline]
[Order article via Infotrieve]
-
Hammami MM, Siiteri PK. Regulation of
11ß-hydroxysteroid dehydrogenase activity in human skin
fibroblasts: enzymatic modulation of glucocorticoid action.
J Clin Endocrinol Metab. 1991;73:326–334.[Abstract]
-
Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y,
Kawamura T, Nyengaard JR, Van den Enden M, Kilo C, Tilton RG.
Hyperglycemic pseudohypoxia and diabetic complications.
Diabetes. 1993;42:801–813.[Abstract]
-
Ido Y, Kilo C, Williamson JR. Cytosolic NADH/NAD, free
radicals, and vascular dysfunction in early diabetes mellitus.
Diabetologia. 1997;40:S115–S117.
This article has been cited by other articles:
|
|
|
|
 
Y. Liu, Y. Nakagawa, Y. Wang, L. Liu, H. Du, W. Wang, X. Ren, K. Lutfy, and T. C Friedman
Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice
J. Mol. Endocrinol.,
August 1, 2008;
41(2):
53 - 64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Liu, Y. Nakagawa, Y. Wang, R. Sakurai, P. V. Tripathi, K. Lutfy, and T. C. Friedman
Increased Glucocorticoid Receptor and 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Hepatocytes May Contribute to the Phenotype of Type 2 Diabetes in db/db Mice
Diabetes,
January 1, 2005;
54(1):
32 - 40.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Liu, Y. Nakagawa, Y. Wang, R. Li, X. Li, T. Ohzeki, and T. C. Friedman
Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice
Diabetes,
June 1, 2003;
52(6):
1409 - 1416.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction