(Hypertension. 2000;36:233.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Antihypertensive Therapy on Renal Injury in Type 2 Diabetic Rats With Hypertension
From the Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark.
Correspondence to A.S. Reddi, MD, PhD, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103. E-mail reddias{at}umdnj.edu
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Abstract |
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Abstract—In a previous study, we demonstrated that doxazocin (DZN), an
1-adrenergic
blocker, prevented proteinuria in streptozotocin diabetic rats. In this
study, we investigated whether DZN would lower established proteinuria
by improving glomerular sclerosis in spontaneously
hypertensive corpulent rats with type 2 diabetes mellitus. DZN
treatment was compared with treatment with
angiotensin-converting enzyme inhibitor,
lisinopril (LIS) alone, and DZN in combination with LIS.
Combination therapy was used to examine any additive effect of either
drug alone in the reduction of proteinuria and glomerular
sclerosis. Both male and female rats age 6 months with established
proteinuria were used. The rats were allocated randomly to 1 of 4
groups: untreated, DZN treated, LIS treated, or a combination of DZN
and LIS treatment. Drug treatment was continued for 16 weeks. The
results show that (1) either drug alone or in combination significantly
lowered systolic blood pressure; (2) DZN, LIS, or combination
therapy reduced albuminuria at 16 weeks of treatment from
baseline by 38.61±5.77%, 30.70±4.21%, and 42.17±4.77% (mean±SE),
respectively. No difference in albuminuria was observed
among the 3 groups of rats; (3) the fractional mesangial
area, which was 20.55±3.77% in untreated rats, was significantly
reduced to 11.18±1.32% in DZN-treated rats, with a further reduction
to 8.72±0.64% in LIS-treated rats and to 3.48±0.35% in rats treated
with DZN+LIS; and (4) DZN but not LIS significantly improved plasma
glucose levels in spontaneously hypertensive corpulent rats (untreated
21.06±0.97 mmol/L versus DZN treated 15.81±0.93 mmol/L or
DZN+LIS treated 17.38±1.10 mmol/L; P<0.025 to
0.005). Thus, the data suggest that 16-week treatment with either DZN
or LIS improves established proteinuria and glomerular
sclerosis, but combination therapy is superior to either DZN or LIS
alone in preventing glomerular sclerosis in type 2 diabetic
rats with hypertension.
Key Words: diabetic nephropathy • rats, spontaneously hypertensive • adrenergic receptor blocker • antihypertensive agents • angiotensin-converting enzyme inhibitors • albuminuria • glomerulosclerosis
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Introduction |
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Diabetes mellitus is the leading cause of end-stage renal disease in the United States.1 Both type 1 and type 2 diabetic patients are at risk for the development of nephropathy because of hyperglycemia and its consequences. Morphologically, either diffuse or selective expansion of the mesangial matrix, which causes obliteration of the capillary lumen and loss of filtration surface area, is characteristic of diabetic nephropathy. Clinically, microalbuminuria, which is defined as urinary albumin excretion of 30 to 300 mg/d, is the hallmark of diabetic nephropathy. Several studies have shown that microalbuminuria can predict the later development of diabetic nephropathy in both types of diabetic subjects.2 3 Prevention of microalbuminuria by good glycemic control was found to preserve renal function and to delay the progression of diabetic nephropathy in animals and human subjects.4 5 6 In addition to hyperglycemia, systemic hypertension can aggravate diabetic nephropathy. Several studies have shown that control of hypertension not only improves proteinuria but also delays the progression of diabetic nephropathy.7 8 9 Among antihypertensive drugs, the angiotensin-converting enzyme (ACE) inhibitors were found to be therapeutically more efficacious in protecting the kidney than other groups of antihypertensive drugs.2 10 11 12 13 However, some calcium blockers,14 15 16
1-blockers,17 18 and
ß-blockers12 19 were also found to prevent proteinuria
in diabetic patients and animals.
We previously reported that doxazosin (DZN), an
1-adrenergic blocker, improves
albuminuria by preventing glomerular loss of
heparan sulfate proteoglycan in streptozotocin diabetic
rats.17 In addition, DZN was found to lower plasma glucose
in these diabetic rats. Drug treatment began 1 week after induction of
diabetes; therefore, DZN improved albuminuria and plasma
glucose by attenuating the rise in blood pressure. It is, however, not
known whether DZN improves proteinuria and plasma glucose in type 2
diabetic rats with established proteinuria and hypertension.
To accomplish this objective, we used spontaneously hypertensive/NIH-corpulent rats (SHR/N-cp) with type 2 diabetes. This rodent model was developed by Dr Carl T. Hansen at the National Institutes of Health (NIH); it was initially bred by mating an obese Koletsky rat to a female SHR of the Okamoto strain.20 After several backcrosses, the resultant SHR/N-cp rats were hypertensive with hyperglycemia, hyperinsulinemia, proteinuria, and glomerular lesions resembling diabetic glomerular sclerosis in humans.20 21 Thus, this rat represents a suitable animal model for the study of proteinuria and associated glomerular sclerosis observed in humans with type 2 diabetes and hypertension. An ACE inhibitor, perindopril, was found to ameliorate glomerular and tubulointerstitial injury in this rat model.22 However, the effect of combination therapy with DZN and an ACE inhibitor on established proteinuria and glomerular sclerosis has not been studied. The purpose of this study was, therefore, severalfold: (1) to examine whether DZN and an ACE inhibitor (lisinopril, LIS) lower blood pressure in SHR/N-cp rats; (2) to investigate whether these antihypertensive drugs improve proteinuria, glomerular sclerosis, and plasma glucose; and (3) to study whether a combination of DZN and LIS is superior to either drug alone in improving proteinuria and glomerular sclerosis.
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Methods |
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Animals
A total of 33 male and female SHR/N-cp rats were used in the study. These rats were initially obtained from Dr Carl T. Hansen. In our laboratory, we selectively inbred rats with plasma glucose levels >12 mmol/L and urine albumin >10 mg/d. After 4 generations of inbreeding, both male and female rats age 24 weeks were randomly divided into 4 groups and allocated to various regimens as follows: 9 rats on DZN (32 mg/100 mL) in tap water, 7 rats on LIS (7 mg/100 mL) in tap water, 8 rats on both DZN and LIS in the above dosages, and 9 rats on tap water. DZN and LIS were first dissolved in distilled water and were made to the required volume with tap water. Water was changed daily for all groups of rats. The daily consumption of DZN and LIS sufficient to lower blood pressure was 12.30±0.87 and 4.57±0.26 mg (mean±SE), respectively. Drug treatment was continued for 16 weeks. All groups of rats were fed Purina rodent chow 5001 ad libitum with the following composition by weight: protein 23.4%, total fat 10%, carbohydrate 49%, and minerals (ash and vitamins) 17.6%. The energy provided was 4.00 kcal/g. The protocol was approved by the Institutional Animal Care and Use Committee (University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark).
Blood Pressure and Urine Collection
Systolic blood pressure was determined in conscious rats
by the tail-cuff method at the beginning of the study and every 4 weeks
until euthanization. At the start and end of the study, each rat was
placed in a metabolic cage for 24-hour urine collection, at
which time body weight and food and water intakes were recorded.
After total volume was measured, the urine was centrifuged and
used for the determination of albumin.
Plasma Glucose and Urinary Albumin
Blood glucose was determined from tail bleeding at the beginning
of the study and every 4 weeks thereafter by the glucose oxidase method
with reagents supplied by Sigma Chemical Co. Urinary albumin
was determined by the radioimmunoassay method of Brodows et
al.23
Glomerular Morphometry
Coronal sections of renal tissue (2 µm thick) were
stained with periodic acid–Schiff stain and were examined by light
microscopy in a blinded fashion. Glomerular volume and
fractional mesangial area measurements were performed by
digital image analysis with the Image-ProPlus (version 3.0)
software system developed by Media Cybernetics. Instrumentation
consisted of a microscope, a microscope-mounted CCD camera (768x493
resolution), and an IBM computer with a color video screen for
projecting and manipulating images. A minimum of 10 glomeruli were
selected randomly for morphometric analysis. Images of
glomeruli at x400 magnification were digitized, presented in
pseudocolor, and saved. The digitized images were then projected on
the computer screen and analyzed at a resolution of 768x493
pixels. The glomerular area or volume, defined as the
cross-sectional area of the renal corpuscle bounded by the Bowman’s
capsule, was determined by manually outlining the Bowman’s capsule on
the image screen with the cursor, and the area was automatically
calculated by the computer. The area of the mesangial
matrix was measured by a pseudocolor image to aid visualization of the
mesangium. The fractional mesangial area was expressed as
the percentage of the glomerular area.
Statistical Analysis
Data were analyzed by 1-way ANOVA for comparisons
between groups and expressed as mean±SE. Significances among groups
were further verified by the Tukey test. Differences within a group
before and after treatment were assessed by Student’s paired
t test. Values were considered significant at
P<0.05.
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Results |
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Table 1 shows pertinent information in various groups of rats at the time of euthanization. No significant differences were found in body weight, kidney weight, daily water intake, food consumption, and urine output between untreated and treated diabetic rats. However, plasma glucose was significantly lower in DZN-treated (P<0.005) and DZN+LIS-treated (P<0.025) groups than in untreated diabetic rats.
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At start, systolic blood pressure was significantly higher in rats allocated to LIS or combination therapy compared with those rats allocated for DZN treatment or for those untreated. In the untreated group, there was a gradual increase in systolic blood pressure (Figure 1). This increase was significantly blunted in rats treated with antihypertensive drugs. A significantly lower systolic blood pressure was observed in LIS-treated rats and in rats that received combination therapy compared with DZN-treated rats; however, no difference was noted between LIS-treated rats and those that received combination therapy. The percent change in albuminuria from baseline at 16 weeks of treatment in various groups is shown in Figure 2. There was an increase of 44.25±21.06% in albuminuria in untreated rats. In contrast, antihypertensive drugs lowered albuminuria by 38.61±5.77%, 30.70±4.21%, and 42.17±4.77%, respectively, in DZN-, LIS-, and DZN+LIS-treated rats. No difference in albuminuria was noted among the 3 groups of diabetic rats.
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Figure 3 shows the fractional mesangial area and glomerular volume in various groups of animals. In untreated rats, this fractional mesangial area composed 20.55±3.77% of the glomerulus, which was significantly reduced to 11.18±1.32% in DZN-treated rats (P<0.05)with further reduction to 8.72±0.64% in LIS-treated rats (P<0.005). The improvement in fractional mesangial area in LIS-treated rats was significant (P<0.001) compared with DZN-treated rats. Combination therapy significantly (P<0.001) reduced the fractional mesangial area to 3.48±0.35% compared with either untreated or treated rats with DZN or LIS. No difference in glomerular volume was observed among the various groups of rats.
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Representative glomeruli from various groups of rats are shown in Figure 4. Untreated diabetic rats demonstrated more deposition of periodic acid–Schiff–positive material than other groups of treated rats. Also, glomerular capillaries were better preserved in treated rats than in untreated rats.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we demonstrated that (1) both DZN and LIS lower blood pressure in SHR/N-cp rats with type 2 diabetes at a mean concentration of 12.30±0.87 and 4.57±0.26 mg/d, respectively; (2) treatment for 16 weeks with DZN, LIS, or a combination of these agents improves established albuminuria; (3) both DZN and LIS decrease glomerular sclerosis significantly, but this decrease is more prominent in rats treated with combined therapy; and (4) only DZN but not LIS lowers plasma glucose levels in these diabetic rats.
This is the first study that showed an improvement in
glomerular sclerosis in diabetic rats by
1-blockade. Although the mechanism of this
improvement is not understood, a recent study demonstrated focal
tubulointerstitial fibrosis and upregulation of
transforming growth factor-ß1
(TGF-ß1) in rats with chronic infusion of
phenylephrine.24 It is possible that
1-blockade decreased the expression of
TGF-ß1 in glomeruli of diabetic rats and thus
improved glomerular sclerosis. This hypothesis is
consistent with the observation of Takahashi et
al,25 who showed the suppression of
TGF-ß1 mRNA expression by prazosin (another
1-blocker) in ventricular myocytes
from hypertrophied hearts. The finding that LIS also improved
glomerular sclerosis is not unexpected, because ACE
inhibitors were found to ameliorate renal injury in both
diabetic and nondiabetic renal diseases2 10 11 12 13 with
downregulation of TGF-ß1 mRNA
levels.26 27 28 Our data support the observations of
Velasquez et al,22 who demonstrated the amelioration of
both glomerular and tubulointerstitial
fibrosis by another ACE inhibitor (perindopril) in these
hypertensive diabetic rats, and the observations of Verseput et
al29 in fawn-hooded rats treated with LIS.
Of interest is the demonstration of minimal glomerular sclerosis with combination therapy. How this combination therapy with similar blood pressure control is superior to either DZN or LIS treatment alone is unclear. However, it is possible that combination therapy may have resulted in normalization of TGF-ß1 and extracellular matrix production. Recent studies have shown that combination therapy (an ACE inhibitor plus a calcium antagonist) is more effective than either drug alone in ameliorating glomerular sclerosis in animals30 or albuminuria in diabetic patients.31 32 33
Albuminuria, the clinical hallmark of diabetic
nephropathy, was equally reduced by DZN, LIS, and
combination therapy. This suggests that not only ACE
inhibitors but also 1-blockers are
effective in reducing established proteinuria in hypertensive type 2
diabetic rats. The mechanisms for the improvement in proteinuria may
relate to the preservation of glomerular heparan sulfate,
as shown with DZN17 and ACE
inhibitors.34 35 Mechanisms such as control of
glomerular hypertension and maintenance of
glomerular capillary permeability and renal autoregulation
may have played a role in reducing albuminuria. Also,
amelioration of glomerular sclerosis may in part be
responsible for the improvement in proteinuria. DZN and prazosin have
been shown to improve albuminuria in hypertensive
patients36 and in patients with kidney
disease,37 although a recent short-term (4 months of
treatment) study failed to demonstrate a reduction in
albuminuria in diabetic patients treated with
DZN.38 However, in this study, when DZN was combined with
an ACE inhibitor (cilazapril), the reduction in
albuminuria was much greater than with either drug alone.
The discrepancy between our study and that of Rachmani et
al38 appeared to be related to the duration of treatment,
because >4 months of treatment in type 2 diabetics causes a
significant reduction in proteinuria by DZN.18
Blood pressure reduction seems to be the major intervention in ameliorating both albuminuria and glomerular sclerosis in DZN- and LIS-treated rats. However, the improvement in glomerular sclerosis with combination therapy compared with LIS therapy with similar blood pressure reduction (Figure 1) implies mechanisms other than blood pressure reduction in preserving renal function. In our study, we measured only systolic blood pressure at 4-week intervals. The use of 24-hour blood pressure monitoring, with telemetry similar to that of Bakris et al,30 may have yielded better blood pressure values in various groups of rats.
A significant decrease in plasma glucose concentration by DZN and not by LIS confirms our similar observation in streptozotocin diabetic rats.17 The mechanism by which DZN improves plasma glucose is unclear. However, DZN has been shown to lower plasma glucose and insulin levels without altering glycosylated HbA1 in type 2 diabetics with hypertension after 6 weeks of treatment.39 Similar results were observed in essential hypertensive subjects treated with DZN for 26 weeks.40 Lithell41 and Kageyama et al42 reported improved insulin sensitivity with euglycemic insulin clamp studies in essential hypertensive subjects after DZN therapy. Giordano et al43 reported increased total body glucose uptake in type 2 diabetic patients with hypertension who were treated with DZN for 12 weeks. These authors reported no effect on fasting plasma glucose of HbA1c concentrations, but the response of glucose to an oral glucose load was significantly improved. This is consistent with studies44 45 that showed improved insulin action in type 2 diabetic patients with hypertension. In contrast, Maheux et al46 demonstrated no effect of DZN on either insulin-mediated glucose disposal or plasma insulin levels in type 2 diabetics with hypertension. However, in nondiabetic hypertensive patients, DZN treatment was associated with a significant improvement in insulin-mediated glucose disposal. Except for this report, the other studies43 44 45 indicate that DZN improves glucose metabolism in patients with type 2 diabetes. Our results of improved circulating glucose levels are consistent with these studies.
In conclusion, the data suggest that DZN and LIS treatments are effective in reducing even established proteinuria, possibly by preserving the diabetes-induced decrease in glomerular heparan sulfate and by ameliorating glomerular sclerosis in hypertensive rats with type 2 diabetes. However, combination therapy was superior to either DZN or LIS treatment in preventing glomerular sclerosis in these rats. The observed effect of DZN in lowering blood glucose levels in the present as well as a previous study17 is an important finding that warrants extensive investigation in diabetic subjects.
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Acknowledgments |
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This study was supported in part by the Kidney Research Foundation of New Jersey, Ruth Papier chapter. The authors thank Dr W. Clark Lambert for help in digital image analysis.
Received December 30, 1999; first decision January 18, 2000; accepted March 8, 2000.
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