(Hypertension. 1997;30:1232-1237.)
© 1997 American Heart Association, Inc.
Articles |
Perindopril Ameliorates Glomerular and Renal Tubulointerstitial Injury in the SHR/N-Corpulent Rat
From the Departments of Medicine and Pathology, George Washington University Medical Center, Washington, DC; Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, Md; University of Maryland, College Park, Md; and Cardiorespiratory Department, Institut De Recherches Internationales Servier & Compagnie-Developpement, Paris, France.
Correspondence to Manuel T. Velasquez, MD, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Ave, NW, Washington, DC 20037.
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Abstract |
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Abstract We compared the effects of long-term treatment with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydrochlorothiazide, reserpine, and hydralazine) on the metabolic and renal features in the SHR/N-corpulent (cp) rat, a genetic model of non–insulin-dependent diabetes mellitus and hypertension. Obese male SHR/N-cp rats (4 to 6 weeks old) were fed a 54% carbohydrate diet containing 18% sucrose and 36% starch. After 2 months on the diet, rats were assigned to one of three groups: one group (n=8) received perindopril (PE); the second group (n=8) received triple therapy (TT); and the third group (n=8) did not receive therapy. Treatment was maintained for 3 to 4 months. Body weight, food intake, and fasting levels of serum glucose and insulin did not differ among the three groups. Control rats exhibited progressive proteinuria in parallel with the rise in systolic blood pressure (SBP). Both PE and TT equally lowered SBP to normal levels and reduced proteinuria in treated rats. However, the reduction of proteinuria was greater and more sustained with PE than with TT (P<.05), whereas the effect of TT on proteinuria was delayed. Plasma renin activity was increased in PE and TT rats compared with control rats (P<.02). Semiquantitative analysis of renal lesions showed that the percentage of glomeruli with mesangial expansion and sclerosis and the tubulointerstitial score (an index of severity of tubulointerstitial lesions, namely tubular atrophy, inflammatory cellular infiltrates, and interstitial fibrosis) was reduced in both PE and TT rats. However, the reduction of glomerulosclerosis and tubulointerstitial lesions was greater in PE than in TT rats (P<.01). The percentage of glomerular sclerosis was positively correlated with the severity score of tubulointerstitial lesions (r=.60, P<.01). We conclude that PE is more effective than TT in halting the progression of proteinuria in the SHR/N-cp rat with non–insulin-dependent diabetes mellitus and hypertension. The antiproteinuric effect of PE is associated with significant reduction in glomerulosclerosis and tubulointerstitial lesions, independent of the effect of treating hypertension.
Key Words: glomerulosclerosis • rats, inbred SHR • angiotensin-converting enzyme inhibition • proteinuria • diabetes mellitus, non–insulin-dependent • renal tubulointerstitium
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Systemic hypertension is considered to be a major risk factor in the development and progression of diabetic nephropathy.1 2 3 4 5 Early clinical studies have shown that when diabetic patients develop hypertension, their renal disease progresses more rapidly.1 4 5 6 7 However, it is unclear from these studies whether the hypertension contributed to acceleration of diabetic nephropathology or occurred as a consequence of diabetic renal disease. There are reports that suggest that the risk of developing renal disease in patients with insulin-dependent diabetes mellitus is closely related to the presence of a predisposition to essential hypertension.8 9 10 Studies in animals with experimental diabetes have also suggested that the presence of hypertension accelerates the progression of nephropathy.11 12 Conversely, effective control of systemic hypertension with antihypertensive agents slows the progression of nephropathy in diabetic patients6 7 13 14 as well as in animals with experimentally induced diabetes.15 16 17 Treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to reduce proteinuria in hypertensive diabetics14 18 19 and to slow the rate of renal functional deterioration in insulin-dependent diabetes mellitus patients with diabetic nephropathy.20 21 22 ACE inhibitors have also been shown to reduce proteinuria and prevent the pathological glomerular changes in rats with experimental diabetes.15 16 17 Whether these beneficial renal effects of ACE inhibitors are specific to this class of agents or due to the nonspecific effects of blood pressure reduction is debatable. Moreover, relatively few data are available regarding the impact of antihypertensive therapy on the development of renal pathologic lesions in non–insulin-dependent diabetes mellitus (NIDDM), which is the more common human type of the metabolic disorder.
The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits both NIDDM and hypertension.23 24 This rat strain was initially bred by mating a male Koletsky rat,25 which was heterozygous for the corpulent gene (cp/+) to a female spontaneously hypertensive rat (SHR/N) derived from the Okamoto strain.26 A minimum of 12 backcrosses were carried out to eliminate the noncorpulent genes of the Koletsky strain. The resultant strain is congenic in which obese homozygotes (cp/cp) are characterized by genetic obesity, hypertension, hyperinsulinemia, and glucose intolerance resembling human NIDDM.27 The obese (cp/cp) rats, in contrast to their lean littermates, develop glucosuria, proteinuria, and renal structural changes marked by enlargement of the kidney and expansion of the glomerular mesangium, which are characteristic features of diabetic nephropathy in humans.27 28
We therefore compared the long-term effects of antihypertensive therapy with an ACE inhibitor, perindopril, and a conventional triple-drug regimen of hydrochlorothiazide (HCTZ), reserpine, and hydralazine on the development of proteinuria and nephropathy in this animal model of NIDDM and hypertension.
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Methods |
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Male obese SHR/N-cp rats were obtained from the National Institutes of Health at approximately 4 to 6 weeks of age and were studied at the Beltsville Human Nutrition Research Center Small Animal Facility, Beltsville, Md. All studies were approved by the Institutional Animal Care and Use Committee and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, Md). Animals were housed individually in stainless steel wire cages in an animal facility with controlled temperature (21°C to 25°C) and relative humidity (40% to 50%) and maintained on a 12-hour dark (9 AM to 9 PM) and light (9 PM to 9 AM) cycle.
Rats were fed a 54% carbohydrate diet containing 18% sucrose and 36% starch plus 10% casein, 10% lactalbumin, 5.9% cellulose, 4% beef tallow, 4% lard, 4% corn oil, 4% hydrogenated coconut oil, 3.1% AIN (American Institute of Nutrition 76) salt mix, and 1% vitamin fortification mix (No. 40060, Teklad Test Diets) and maintained on this diet throughout the study. After 2 months on the diet, rats were divided into three groups: one group (n=8) was assigned to treatment with the ACE inhibitor perindopril (Servier, Neuilly, France); the second group (n=8) was assigned to receive triple-drug therapy with HCTZ, reserpine, and hydralazine; and the third group (n=8) did not receive therapy and served as time controls. Perindopril (0.25 to 0.5 mg/kg body wt per day) and triple drugs 30 mg/L HCTZ, 4 mg/L reserpine, and 50 mg/L hydralazine) were administered daily in the drinking water for a period of 3 to 4 months. Water intake was measured daily, and dosages of perindopril and triple drugs were adjusted to maintain systolic pressure to less than 140 mm Hg but above 110 mm Hg.
Throughout the study, food intake, body weight, and systolic blood pressure (SBP) by the tail-cuff method29 were measured biweekly in each animal. Blood samples for determination of serum glucose and insulin were obtained by tail bleeding. Urine collections for measurement of urinary protein excretion were made as follows. Six hours into the dark cycle, nonfasted rats were placed in individual metabolic cages and kept without food for 17 hours. Urine was collected for 17 hours in bottles containing 2 mL of mineral oil. Fasting levels of serum glucose and insulin and urinary protein excretion were measured before and at 2 to 4 weekly intervals during treatment. At the end of the drug treatment period, a blood sample for determination of plasma renin activity (PRA) was also obtained. After blood and urine collections were completed, rats were killed. The kidneys were immediately perfused through the descending aorta with 0.9% saline solution followed by a solution containing zinc-formalin fixative (Anatech, Ltd) using a Cole-Palmer peristaltic pump (Cole-Palmer Instrument Co) set to deliver 10 mL volume per minute at physiological pressures. At the end of perfusion, the kidneys were removed, weighed, and processed for histologic examination.
Metabolic and Renal Functional Measurements
Serum glucose concentration was measured by a hexokinase method
described by Bondar and Mead.30 Serum insulin was measured
by radioimmunoassay using human insulin as standard.31 PRA
was determined by radioimmunoassay.32 Urine protein
concentration was determined by a modification of the Lowry
method.33
Renal Morphology
Coronal sections of the in situ perfusion-fixed kidney were
prepared for histology as described previously.28 The
paraffin-embedded tissue was sectioned at 2 to 3 µm and stained
with hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), Masson's
trichrome, and periodic acid methenamine (PAM) silver stains. All
specimens were evaluated blindly by the same observer. The
glomerular lesions were evaluated in the following manner.
Slides were inserted into the micrometer stage of a Zeiss
model 16 microscope equipped with Neofluar lenses and scanned in passes
at about a 2-mm distance per pass at x250 magnification. For each
specimen, 100 glomeruli were scanned first for morphological
evaluation. Glomerular morphology was evaluated as follows.
Glomeruli were evaluated as showing: (1) normal morphology; (2)
segmental expansion of mesangium; (3) diffuse expansion of mesangium;
or (4) intercapillary nodules. Glomeruli in fields of
tubulointerstitial inflammation with
periglomerular fibrosis and/or segmental or global
sclerosis were counted separately. The number of glomeruli with normal
morphology and with the above lesions was tabulated using a manual
counter and expressed as percentage. The PAS, Masson's trichrome, and
PAM silver stains were used to assess the extent of
mesangial expansion and confirm the presence of
glomerular sclerosis.
The renal interstitium was evaluated semiquantitatively using a grading system with a score of 0 to 4+, which assessed the tubules and the interstitium for the presence of (1) tubular atrophy; (2) tubular dilatation; (3) interstitial inflammatory cell infiltrates; and (4) interstitial fibrosis. A score of 0 indicated no lesion (normal kidney); 1+ indicated a single, small focal lesion with very minimal tubular alterations and interstitial inflammatory cell infiltration; and 2+ to 4+ indicated increasing severity of tubular lesions, interstitial inflammatory cell infiltration, and/or fibrosis. A score of 4+ was arbitrarily assigned when approximately 50% or more of the renal parenchyma or interstitium was involved.
Statistical Analysis
Results are expressed as mean±SEM. Comparisons among the groups
were made using one-way ANOVA followed by Student's t test
if differences were noted. Simple regression analysis was used
for calculation of the correlation coefficient. Statistical
significance was defined as P<.05.
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Results |
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The serial values of body weight, food intake, SBP, and urinary protein excretion in control, perindopril-treated (PE), and triple drug-treated (TT) obese SHR/N-cp rats are shown in Fig 1
. Body weight gain and food intake did
not differ among the three groups throughout the study. In control
rats, SBP rose gradually from a mean of 143 mm Hg at baseline to
between 170 and 180 mm Hg at the end of the study. In PE and TT
rats, however, SBP was reduced to below 140 mm Hg but above
110 mm Hg throughout treatment. Mean SBP did not differ between
PE and TT rats. In control rats, urinary protein excretion increased
progressively throughout the study. In contrast, urinary protein
excretion was markedly reduced in PE rats and was maintained below the
baseline throughout the treatment period. In TT rats, however,
proteinuria increased initially during the first 4 to 6 weeks of
therapy but later decreased toward baseline values after 8 to 10 weeks
of treatment. At 12 to 14 weeks of therapy, urinary protein excretion
was significantly lower in TT rats than in control rats
(P<.05) but was slightly higher compared with corresponding
values in PE animals (P<.05). Fasting levels of serum
glucose and insulin measured before and during the treatment period did
not differ among the three groups (Table 1). PRA measured at the end of the drug
treatment period was significantly higher in both PE and TT rats
compared with controls (52±8 and 38±2, respectively, versus 11±2 ng
angiotensin
I · mL-1 · h-1,
P<.02).
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Fig 2 shows the typical renal lesions of
obese SHR/N-cp rats. The glomeruli of untreated rats show segmental or
diffuse mesangial expansion and sclerosis (Fig 2A and 2B).
The tubulointerstitium shows focal areas of tubular dilatation
and atrophy with or without proteinaceous material in lumina,
inflammatory cellular infiltrates, and interstitial
fibrosis. Abnormal and sclerosed glomeruli are often seen adjacent to
foci of tubulointerstitial lesions. By contrast,
both glomerular and tubulointerstitial
changes were less prominent in PE rats (Fig 2C and 2D) and TT rats (not
shown in the figure) than in control animals. Differences between PE
and TT rats were not readily apparent from this qualitative
assessment.
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Semiquantitative analysis of renal lesions are shown in Table 2. Mean kidney weight was slightly lower
in PE and TT rats than in control rats, but the differences were not
statistically significant. In control rats, about 31% of glomeruli
counted showed lesions consisting of segmental or diffuse
mesangial expansion, whereas in PE and TT rats, the number
of glomeruli showing the same lesions was less, eg, 14% and 17%,
respectively (P<.05, compared with control rats). In
contrast, the percentage of glomeruli showing sclerosis was
significantly reduced in PE rats with a mean value of 4±1%
compared with 16±3% in control rats (P<.05) and was lower
than that (9±4%) in TT rats (P<.05). Both PE and TT rats
also had significantly lower tubulointerstitial
scores compared with control rats (P<.01), with PE animals
showing the lowest score that is also significantly different from TT
rats (P<.01) (Table 2 and Fig 3). There was a significant positive
correlation between percentage of glomerular sclerosis and
tubulointerstitial score (r=.60,
P<.01).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we compared the long-term effects of antihypertensive treatment with the long-acting ACE inhibitor perindopril and triple therapy with HCTZ, reserpine, and hydralazine on metabolic and renal features in obese SHR/N-cp rats with NIDDM that develop proteinuria and renal morphological changes resembling human diabetic nephropathy. Because this rat strain also develops hypertension that is presumably genetically determined, our goal was to normalize blood pressure to between 110 and 140 mm Hg systolic to determine whether controlling hypertension with differing therapies in this model can prevent or halt the development of nephropathy. Indeed, untreated obese SHR/N-cp rats exhibited progressive proteinuria in parallel with the development of hypertension. In contrast, both perindopril treatment and triple therapy equally reduced SBP to normal levels in obese rats. Chronic perindopril treatment, however, resulted in a sustained reduction in proteinuria and halted its progression. Triple therapy in obese rats also caused a significant decrease in proteinuria, but this effect was less compared with perindopril treatment and was not apparent until after 12 to 14 weeks of therapy. The reduction of proteinuria by perindopril and triple therapy was associated with significant decreases in the number of glomerular lesions, namely mesangial expansion and glomerular sclerosis. However, perindopril treatment limited glomerular sclerosis to a greater extent than triple therapy.
These results are in agreement with those of Anderson and co-workers15 who compared the effects of captopril and triple therapy in moderately hyperglycemic Munich-Wistar rats with streptozotocin (STZ)–induced diabetes. These investigators showed that both regimens equally reduced systemic arterial pressure but that captopril was more effective than triple therapy in preventing albuminuria and glomerulosclerosis in the diabetic rats, confirming earlier observations with enalapril in this model.34 However, studies by Cooper et al17 comparing perindopril and triple therapy in SHR rats made diabetic with STZ showed that both forms of therapy were equally effective in reducing systemic arterial pressure and albuminuria. This same group of investigators used the same regimens in normotensive, STZ-induced diabetic Sprague Dawley rats and found similar reductions of blood pressure and albuminuria with both treatments.35 The reasons for these discrepant results are not clear but may be partly related to differences in rat strain or the degree of hyperglycemia among the diabetic models. The obese SHR/N-cp rats used in the present study were markedly hyperinsulinemic and mildly hyperglycemic. Perindopril treatment and triple therapy had no appreciable effect on levels of serum glucose and insulin in these animals. Therefore, the differing renal effects of perindopril and triple therapy cannot be ascribed to differences in the glycemic state of the animals. Similarly, because food intake and body weight were not significantly reduced by either perindopril or triple therapy, it is also unlikely that the improvement of proteinuria observed with both regimens is related to reductions in caloric and/or protein intake.
In the present study, both perindopril and triple therapy produced marked increases in PRA. The increase in PRA induced by perindopril is most likely due to a compensatory response to a decrease in angiotensin II formation caused by ACE inhibition. On the other hand, the rise in PRA associated with triple therapy is probably the result of direct stimulation of renin secretion induced by HCTZ and hydralazine. Because ACE is not inhibited by these two agents, the increased renin release would be expected to result in an increase in angiotensin II production. It is possible that the greater reduction of proteinuria by ACE inhibitors may be related to inhibition of angiotensin II–mediated effects on the kidney. Whatever the mechanisms underlying the inhibitory effects of ACE inhibitors on proteinuria, our results support the view that ACE inhibitors have an additional renal protective effect independent of their antihypertensive properties.
Most previous studies on the pathogenesis of diabetic nephropathy have focused primarily on the alterations in glomerular structure and function.36 37 38 39 40 However, only a few studies have stressed the importance of the involvement of nonglomerular structures in the diabetic kidney.41 42 43 44 45 Bader and coworkers41 have shown a close correlation between interstitial expansion and progression of glomerular sclerosis. Similarly, Mauer and coworkers44 observed a direct correlation between index of mesangial expansion and index of interstitial fibrosis in insulin-dependent diabetes mellitus patients with varying degrees of nephropathy. In this study, interstitial fibrosis was present even at the earliest stages of diabetic nephropathy, and mesangial expansion was more extensive in those patients with hypertension, overt proteinuria, and low glomerular filtration rate. As glomerular filtration rate fell, the interstitial fibrosis was also noted to be more prominent. As in a previous study,28 we also observed abnormalities in the renal tubulointerstitium of obese SHR/N-cp rats consisting of tubular dilatation and atrophy, focal inflammatory cell infiltration, and interstitial fibrosis. These changes are often seen in areas with increased number of abnormal and sclerosed glomeruli. In the present study, both perindopril and triple therapy also significantly reduced the severity of tubulointerstitial lesions, but the magnitude of reduction was greater with perindopril compared to triple therapy. Moreover, we found a positive correlation between the percentage of glomerular sclerosis and the degree of tubulointerstitial involvement. These observations, however, do not in any way distinguish whether the tubulointerstitial pathology is primary or secondary to glomerular damage but raise the possibility that the development of glomerulosclerosis and tubulointerstitial lesions in the diabetic kidney may have a common pathophysiologic mechanism.
In summary, the present results have shown that effective control of hypertension reduces proteinuria and the severity of glomerular and tubulointerstitial lesions in the SHR/N-cp rat, a genetic animal model of NIDDM and hypertension. Our results, however, also indicate that treatment with perindopril is more effective than triple therapy in halting the progression of proteinuria in NIDDM, independent of its effect on hypertension. These studies provide further evidence that the protective effect of ACE inhibitors on the kidney in NIDDM is associated with a significant reduction in glomerulosclerosis and tubulointerstitial lesions.
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Acknowledgments |
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This study was supported in part by a research grant from Institut de Recherches Internationales Servier, Paris, France. We thank Razia Husein for technical assistance.
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Footnotes |
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1 Deceased.
Received April 24, 1997; first decision May 14, 1997; accepted May 29, 1997.
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References |
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