(Hypertension. 1996;27:1108-1114.)
© 1996 American Heart Association, Inc.
Articles |
Doxazosin Prevents Proteinuria and Glomerular Loss of Heparan Sulfate in Diabetic Rats
From the Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.
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Abstract |
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Abstract We examined whether blood pressure reduction or good glycemic control equally lower albuminuria by preventing glomerular loss of heparan sulfate and progression of glomerulosclerosis in streptozotocin-induced diabetic rats. We used doxazosin, an
1-adrenergic blocker, to lower systemic blood pressure,
and good glycemic control was achieved by insulin treatment. Rats were
killed after 20 weeks of treatment. Doxazosin significantly lowered
systolic pressure in diabetic rats; however, it had no effect
in normal rats. Good glycemic control also lowered systolic
pressure. In diabetic rats with good glycemic control, doxazosin had an
additive effect on blood pressure. Glomerular heparan
sulfate synthesis was significantly lower and urinary albumin
excretion higher in diabetic than in normal rats. Both doxazosin
treatment and good glycemic control normalized these abnormalities in
diabetic rats. Insulin normalized plasma glucose and glycosylated
HbA1 concentrations in diabetic rats, as did doxazosin.
Significant increases in mesangial area and
glomerulosclerosis were observed in diabetic
rats. Only good glycemic control normalized these pathological changes
in all diabetic rats. Two-way factorial ANOVA showed an interaction
between the effects of doxazosin and insulin on systolic
pressure and plasma glucose. The data show that after 20 weeks of
doxazosin treatment, albuminuria was reduced by 80%;
however, this treatment had no significant effect on
mesangial expansion or progression to
glomerulosclerosis. Conversely, good glycemic
control prevented all three of the preceding sequelae.
Key Words: diabetic nephropathy • blood pressure • adrenergic alpha-antagonists • antihypertensive therapy • albuminuria • rats
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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 Renal disease in insulin-dependent diabetic subjects follows a predictable course from the onset of glomerular hypertrophy and hyperfiltration to the progression of microalbuminuria to macroalbuminuria and finally azotemia, which eventually leads to end-stage renal disease.2 Microalbuminuria (urinary albumin excretion of 30 to 300 mg/d) indicates the escape of albumin across the GBM, which is the only anatomic barrier between blood and urine. In diabetes, the structure and function of the GBM are altered.3 As a result, it becomes less of a barrier to the leakage of albumin.3 4
Microalbuminuria has been shown to be a predictor of later development of glomerulosclerosis in both insulin-dependent and non–insulin-dependent diabetic subjects.5 6 7 8 9 Prevention of microalbuminuria or macroalbuminuria by either GGC4 10 11 12 or antihypertensive drugs13 14 15 was found to preserve renal function or delay the progression of diabetic glomerulosclerosis in both animals and human subjects. Among antihypertensive drugs, the angiotensin-converting enzyme inhibitors (ACE inhibitors) have been extensively studied16 17 18 19 20 21 and found to be therapeutically more efficacious in protecting the kidney than other groups of antihypertensive drugs.21 Also, some but not all calcium entry blockers have been shown to improve proteinuria in diabetic patients22 23 and animals.24 25
Although microalbuminuria seems unquestionably to be the predictor of glomerulopathy,8 the mechanisms for this microalbuminuria are incompletely understood. One of the suggested mechanisms is the altered synthesis of glomerular heparan sulfate proteoglycan.26 This heparan sulfate confers a negative charge to the GBM, and the loss of electronegativity plays a major role in regulating albumin escape into the urinary space. It has been shown, for example, that depletion of heparan sulfate in the GBM by treatment with heparinase results in an increased permeability to 125I-labeled albumin.27 Also, a study by Van Den Born et al28 showed that administration of a monoclonal antibody against GBM heparan sulfate induced an increase in urinary albumin excretion in rats. In human diabetic subjects, a decreased content of heparan sulfate has been demonstrated in the GBM.4 29 Other evidence, consistent with this finding, is that decreased synthesis of renal proteoglycan has been reported in diabetic rats30 31 32 33 and in Engelbreth-Holm-Swarm tumor grown in genetically diabetic mice.34
Since our previous studies demonstrated a decrease in
glomerular synthesis of heparan sulfate associated with
significant albuminuria in long-term diabetic rats and
these changes were prevented by ACE
inhibitors35 36 and a calcium entry
blocker,25 we thought it of interest to study whether an
1-blocker such as DZN would similarly prevent the renal
loss of heparan sulfate and albumin. Therefore, the objectives
of this study were (1) to examine the efficacy of DZN in lowering blood
pressure in diabetic rats; (2) to study the effect of this
1-blocker on glomerular synthesis of heparan
sulfate, albuminuria, and mesangial area; and
(3) to examine whether DZN is as efficacious as GGC in preventing
albuminuria by improving glomerular synthesis
of heparan sulfate and glomerular changes in diabetic
rats.
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Methods |
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Animals
A total of 56 male Wistar rats (Charles River Laboratories, Wilmington, Mass) weighing 80 to 100 g were used in the study. After rats had fasted overnight, diabetes was induced in 36 rats with a single intraperitoneal injection of streptozotocin in 0.1 mmol/L citrate buffer, pH 4.5, at a concentration of 60 mg/kg body wt. The remaining 20 rats received an equivalent amount of buffer and served as normal control rats. One week after induction of diabetes, the diabetic rats were randomly divided into four groups and allocated to various regimens as follows: 10 rats on DZN (75 mg/L), 8 rats on ultralente insulin (Illetin 1, Eli Lilly & Co) to maintain near normoglycemia (GGC), 10 rats on insulin plus DZN (75 mg/L) (GGC+DZN), and 8 rats on tap water. Of the 20 normal rats, 10 received DZN (75 mg/L) and the remaining 10 received only tap water. This DZN dose was found to be effective in lowering blood pressure in diabetic rats. DZN was first dissolved in distilled water and made up to the required volume with tap water. GGC and GGC+DZN rats received 2 to 10 U insulin SC daily for maintenance of blood glucose levels between 8 and 10 mmol/L. The initial insulin requirement for maintenance of blood glucose levels near normal was 10 U per rat per day, which gradually decreased to 2 U. Blood glucose from the tail vein was determined initially every 2 days for 1 week and subsequently every 4 weeks with a glucometer (Ames) in all rats. Drug treatment was continued for 20 weeks. Water was changed daily in all rat groups. The daily consumption of DZN in different rat groups was as follows (mean±SE): normal rats, 2.8±0.2 mg; diabetic rats, 13.2±0.4 mg; and GGC+DZN rats, 5.7±0.4 mg. All rat groups were fed Purina rodent chow 5001 ad libitum with the following composition by weight: protein, 23.4%; fat, 4.5%; crude fiber, 5.8%; sodium, 0.4%; calcium, 1%; phosphorus, 0.61%; and potassium, 1.1%, with vitamin supplementation. The energy provided was 4.25 kcal/g.
Blood Pressure Measurements and Urine Collection
Systolic pressure was measured in conscious rats by the
tail-cuff method. At 20 weeks, 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, Glycosylated HbA1, Plasma
Immunoreactive Insulin, and Urinary Albumin
Immediately before death, each rat was anesthetized with
an intraperitoneal dose of ketamine HCl
(0.1 mL/100 g), and blood was drawn into a heparinized syringe from the
heart and centrifuged at 1500g for 10 minutes.
Plasma glucose was determined by a glucose oxidase method with the
reagents supplied by Sigma Chemical Co. Glycosylated HbA1
was determined by a glycogel test kit (Pierce Chemical Co). Plasma
immunoreactive insulin levels were determined by a double-antibody
radioimmunoassay method (Pharmacia Diagnostics). Urinary
albumin was determined by the radioimmunoassay method of
Brodows et al.37
Glomerular Heparan Sulfate Synthesis
The methods used for isolation of glomeruli and determination of
heparan sulfate synthesis have been described in detail
elsewhere.25 Briefly, soon after rats were
anesthetized, the kidneys were excised and weighed, and a piece
of the tissue was fixed in 10% neutral formalin. The medulla and
cortex were removed from each kidney. Cortices were minced and
sequentially sieved through 150-, 250-, and 63-µm sieves with the use
of ice-cold 0.02 mol/L phosphate-buffered saline, pH 7.2, and
pellets were obtained by centrifugation.
After centrifugation, the glomerular pellets were washed twice with Krebs-Ringer solution, and the washed glomeruli were resuspended in the same solution. Concentrations of glomeruli were determined by counting under a microscope, and a volume containing approximately 104 glomeruli was incubated in 2.0 mL glutamine-ascorbate–enriched Krebs-Ringer solution containing 50 µCi [35S]sulfate (specific activity=788 mCi/[mmol/L]) for 4 hours at 37°C. The reaction was terminated by the addition of 1 mmol/L puromycin. Samples were centrifuged to produce pellets, treated with acetone to remove lipids, dried, and weighed. Glycoproteins were released by incubation with papain/EDTA and GAGs precipitated with 10% cetylpyridinium chloride.25 Proteins were separated out with 10% trichloroacetic acid treatment. GAGs were precipitated from the supernatant with NaCl/ethanol and dissolved in distilled water, and 0.1 mL was taken for determination of radioactivity. This represented counts in total GAG. For identification of individual GAGs, another aliquot was treated with 5 mg testicular hyaluronidase and 200 µg chondroitinase-ABC (Sigma) in 0.15 mol/L NaCl and 0.1 mol/L acetate buffer, pH 5.6, at 37°C for 24 hours for removal of chondroitin and dermatan sulfates. Digested material (0.2 mL) was passed onto a Sephadex column; the heparan sulfate fraction was eluted with 0.15 mol/L NaCl in 10% ethanol; and the radioactivity was determined in the eluted fraction. The presence of heparan sulfate in the void volume was verified by its resistance to testicular hyaluronidase and its degradation by nitrous acid. Total GAG synthesis is expressed as disintegrations per minute per milligram glomerular weight or per glomerulus. Heparan sulfate and chondroitin sulfate are expressed as percentage of total GAGs.
Histology
Coronal sections of renal tissue (2 µm thick) were stained
with periodic acid–Schiff and examined by light microscopy in a blind
fashion. In each tissue section, at least 50 glomeruli were examined
for the presence of glomerulosclerosis, which
was defined as collapse of the glomerular capillary lumens
and replacement by periodic acid-Schiff–positive material. The
number of glomeruli with any evidence of sclerosis was divided by the
total number of glomeruli examined for determination of the percentage
of sclerotic glomeruli.
Planar areas of the glomerular capillary tufts were measured in nonsclerotic glomeruli with the use of a digital tablet in combination with a video-displayed morphometric computer program to obtain the glomerular area using a point counting technique38 (Microcomp DS and PM-2, Southern Micro Instruments). With the same program, the mesangial regions were identified by gray scale thresholding, and a pseudocolor mask was used to aid visualization of the mesangium. The fraction of the glomerular tuft area occupied by a predetermined range of color shades was expressed as the fractional mesangial area. A minimum of 32 (range, 32 to 72) glomeruli in each tissue specimen were examined for glomerular tuft area and fractional mesangial area.
Statistical Analysis
Data presented in Tables 1
and 2 and Figs 1 and 2 were
analyzed by one-way ANOVA. Statistical significance was
analyzed by the Tukey test and verified by Student's
t test. The main effects of DZN or insulin treatment alone
and in combination on data obtained at the end of the study in diabetic
rats (Table 3) were determined by two-way factorial ANOVA followed
by comparison between mean values with application of Duncan's test.
The data included systolic pressure, albuminuria,
heparan sulfate synthesis, plasma glucose, glycosylated
HbA1, mesangial area,
glomerular area, and
glomerulosclerosis. All percentage data were
transformed to their arcsine for normal distribution before two-way
ANOVA was performed. Data are expressed as mean±SE; a value of
P<.05 was considered significant.
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Results |
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Table 1
shows pertinent data in various rat groups
at the end of the experimental period. Diabetic rats had significantly
lower body weights and plasma insulin levels but higher kidney weights
than normal rats. Insulin treatment normalized all these
parameters. In diabetic rats, DZN normalized kidney weight.
Although body weight was not normalized, it was significantly improved
by DZN treatment in these rats compared with untreated diabetic rats.
DZN had no effect on plasma insulin levels in either normal or diabetic
rats. Food intake was significantly higher in diabetic than normal or
insulin-treated diabetic rats. Water consumption and urine volumes
were higher in diabetic than normal rats. Although insulin treatment
normalized water intake and urine volume in diabetic rats, DZN
significantly lowered these parameters.
The incorporation of [35S]sulfate into total GAG, heparan
sulfate, and chondroitin sulfate by isolated glomeruli in various rat
groups is shown in Table 2. A significant decrease in
incorporation into total GAG, when expressed either per milligram dry
glomerular weight or per glomerulus, was found in diabetic
compared with normal rats. Similarly, a decrease in heparan sulfate
synthesis also was found in diabetic rats. In contrast, the
incorporation into chondroitin sulfate was significantly increased in
diabetic rats. DZN treatment or control of blood glucose with insulin
returned these changes toward normal. Glomerular weights
did not differ significantly between normal and treated diabetic
rats.
The interaction between the effects of DZN and insulin on various
parameters in diabetic rats is shown in Table 3. Results showed an interaction between these two
treatments on systolic pressure, albuminuria,
plasma glucose, and glycosylated HbA1. This interaction was
found to be positive and multiplicative on blood pressure and plasma
glucose, whereas the interaction on albuminuria and
glycosylated HbA1 was not multiplicative. No interaction of
DZN and insulin could be observed on heparan sulfate synthesis and
histological changes of the kidney.
Systolic pressures, plasma glucose levels, glycosylated
HbA1 values, and 24-hour urinary albumin levels in
various rat groups are shown in Fig 1. These
parameters were significantly higher in diabetic than
normal rats. Insulin treatment normalized all of them, whereas DZN
significantly lowered plasma glucose and glycosylated HbA1
but normalized systolic pressure and urinary albumin
levels.
The fractional mesangial area, incidence of
glomerulosclerosis, and glomerular
area are given in Fig 2. As shown, the
mesangial area and percentage of
glomerulosclerosis were significantly higher in
diabetic than normal rats. GGC normalized these pathological changes.
Although DZN treatment improved both the mesangial area and
glomerulosclerosis, the mean decrease was not
statistically significant. However, 3 of 10 DZN-treated diabetic rats
showed no evidence of glomerulosclerosis. In
contrast, all diabetic rats had demonstrable
glomerulosclerosis (4% to 23%; mean±SE,
9.34±0.31%). No statistically significant difference in
glomerular area was observed in any of the groups
studied.
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Discussion |
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This study demonstrates several important observations: (1) DZN lowers blood pressure in diabetic rats at a mean concentration of 13.2±0.4 mg/d; (2) the observed decrease in glomerular heparan sulfate synthesis in diabetic rats is ameliorated but not prevented by DZN; (3) albuminuria, which is increased in diabetic rats, is normalized by long-term treatment with DZN; (4) long-term treatment with DZN improves not only circulating levels of glucose but glycosylated HbA1 in diabetic rats, without significantly increasing insulin levels; and (5) DZN effects on blood pressure and albuminuria are comparable to the effects of GGC in diabetic rats.
Although insulin reverses hyperglycemic induction of proteinuria, the mechanisms by which DZN lowers proteinuria in diabetic rats are not completely understood. However, the results of the present study indicate that DZN prevents the glomerular loss of heparan sulfate and thus prevents the leakage of albumin through the GBM. This supports the theory of charge selectivity as a mechanism for proteinuria in diabetic renal disease.25 26 27 28 The GBM also acts as a size-selective barrier to protein leakage.39 40 In diabetes, the pore size of the GBM is increased, thus allowing large molecules such as albumin to pass through it.39 40 It is possible that DZN may have affected the pore size of the GBM favorably, thus impeding the passage of albumin. Since glomerular pressures and flows are elevated in diabetic rats41 42 as well as dogs43 and these parameters were not measured in the present study, it is difficult to speculate whether DZN improved these hemodynamic parameters with subsequent improvement in albuminuria. However, DZN lowered arterial blood pressure, which in turn may have caused a favorable change in pressure-induced biochemical abnormalities in the glomerulus.44 Another possible mechanism for improvement in albuminuria may have been a reduction in the glycosylation of albumin induced by DZN, since glycosylated albumin can leak through the GBM easily.45 46 The observed reduction in glycosylated HbA1 supports this contention.
To our knowledge, this is the first report demonstrating the beneficial effect of DZN on albuminuria in diabetic animals. A similar effect of DZN on microalbuminuria was reported in essential hypertensive subjects after 12 weeks of treatment.47 Such a study has not been conducted in diabetic subjects.
DZN has been shown to lower plasma glucose and insulin levels without altering glycosylated HbA1 in non–insulin-dependent diabetics with hypertension after 6 weeks of treatment.48 Similar results were observed in essential hypertensive subjects treated with DZN for 26 weeks.49 Lithell50 and Kageyama et al51 reported improved insulin sensitivity using euglycemic insulin clamp studies in essential hypertensive subjects after DZN therapy. Recently, Giordano et al52 reported increased total body glucose uptake in non–insulin-dependent diabetic patients with hypertension who were treated with DZN for 12 weeks. These authors reported no effect on fasting plasma glucose or HbA1c concentrations, but the response of glucose to an oral glucose load was significantly improved. This is consistent with an earlier study53 that showed improved insulin-mediated glucose disposal in non–insulin-dependent diabetic patients with hypertension. In contrast, Maheux et al54 demonstrated no effect of DZN on either insulin-mediated glucose disposal or plasma insulin levels in non–insulin-dependent diabetics with hypertension. However, in nondiabetic hypertensive patients, DZN treatment was associated with a significant improvement in insulin-mediated glucose disposal.54 Except for this report, the other two studies52 53 indicate that DZN improves glucose metabolism in patients with non–insulin-dependent diabetes. Our results of improved circulating glucose levels are consistent with these two studies. Furthermore, DZN has an additive effect on glucose levels when combined with insulin treatment. Our rats are insulinopenic; therefore, the effect of DZN on circulating insulin levels cannot be assessed.
The observation of an increase in the fractional mesangial area in diabetic rats and its normalization by GGC is consistent with an earlier report by Steffes et al.55 Also, the finding that GGC improves proteinuria in diabetic subjects has been elegantly shown by several recent studies.10 11 12 Our data further support these studies. Unlike GGC, DZN did not normalize either mesangial expansion or glomerulosclerosis. Unlike systolic pressure, there was no interaction between DZN and insulin on histological changes of the kidney. The mean glomerular area was not significantly increased in diabetic rats. The reason is unclear; however, diabetic rats that were treated with insulin but maintained moderate hyperglycemia do not exhibit an increase in glomerular volume.56
Although a relationship between increases in proteinuria and the extent of glomerulosclerosis has been demonstrated, dissociation between these two parameters has also been reported in diabetic dogs.43 57 Gaber et al57 reported a decrease in proteinuria but an increase in global glomerulosclerosis in diabetic dogs treated with a diltiazem-like (TA3090) calcium blocker. Our data of reduced proteinuria with no significant improvement in either mesangial area or glomerulosclerosis in DZN-treated diabetic rats are consistent with these findings.
It is of interest that either DZN or GGC, by normalizing systemic blood pressure (and possibly glomerular capillary pressure) and/or glomerular heparan sulfate synthesis, protects against the development of albuminuria in diabetic rats. However, only GGC reduces plasma glucose levels sufficiently that mesangial area and glomerulosclerosis are reduced. Thus, the data suggest that a dissociation can occur in diabetes between albuminuria and the extent of glomerular histological injury when only blood pressure and not plasma glucose is adequately controlled and support a primary role for metabolic alterations in the development of diabetic glomerulosclerosis. Importantly, from a clinical perspective, by looking only at effects on albumin excretion, one cannot necessarily conclude that an agent is exerting a beneficial action to reduce glomerular structural injury.
The results of the present study are significant for several reasons: (1) this is a long-term study in moderately hyperglycemic rats without the use of insulin for survival; (2) no study has compared DZN with GGC on albuminuria or morphometry of the glomerulus in diabetic rats; (3) variables such as food intake and water consumption that could adversely affect albuminuria were controlled in the present study; and (4) the effect of DZN in lowering glycosylated HbA1 is a unique observation that has not been reported in any previous study.
DZN is as effective as other antihypertensive drugs such as angiotensin-converting enzyme inhibitors and some calcium entry blockers in lowering proteinuria in diabetic rats. Also, the antialbuminuric effect of DZN is comparable with that of GGC in diabetic rats. Whether such a similarity could be demonstrated in diabetic humans remains to be seen.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to thank Sarah S. Suarez, Parul Patel, and Rajeth Koneru for their technical assistance and Dr Burton Fine for his help in the statistical evaluation of the data.
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Footnotes |
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Reprint requests to A.S. Reddi, MD, PhD, Department of Medicine, UMDNJ, New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103.
Received December 14, 1995; first decision January 8, 1996; accepted February 6, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. United States Renal Data System 1991 Annual Data Report. Am J Kidney Dis. 1991;18(suppl 2):1-127.
2. Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease: with emphasis on the stage of incipient nephropathy. Diabetes. 1983;32(suppl 2):64-78.
3. Olson JL. Diabetes mellitus. In: Heptinstall RH, ed. Pathology of the Kidney. Boston, Mass: Little, Brown & Co; 1992:1715-1763.
4.
Reddi AS, Camerini-Davalos RA. Diabetic
nephropathy: an update. Arch Intern Med. 1990;150:31-43.
5. Viberti GC, Jarrett RJ, Mahmud U, Hill RD, Argyropoulos A, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1:1430-1432. [Medline] [Order article via Infotrieve]
6.
Parving H-H, Oxenboll B, Svendsen PA, Christiansen JS,
Andersen AR. Early detection of patients at risk of developing
diabetic nephropathy: a longitudinal study of urinary
albumin excretion. Acta Endocrinol (Copenh). 1982;100:550-555.
7. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984;311:89-93. [Abstract]
8. Mogensen CE. Prediction of clinical diabetic nephropathy in IDDM patients: alternatives to microalbuminuria? Diabetes. 1990;39:761-767. [Abstract]
9.
Abbott KC, Sanders LR, Bakris GL.
Microalbuminuria in non-insulin-dependent
diabetes mellitus: implications for renal survival. Arch
Intern Med. 1994;154:146-153.
10. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control of late complications of type I diabetes. Lancet. 1993;341:1306-1309. [Medline] [Order article via Infotrieve]
11. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Trial. Kidney Int. 1995;47:1703-1720. [Medline] [Order article via Infotrieve]
12. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. 1995;18:258-268. [Abstract]
13. Mogensen CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial antihypertensive treatment. Scand J Clin Lab Invest. 1976;36:383-388. [Medline] [Order article via Infotrieve]
14. Parving H-H, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet. 1983;2:1175-1179. [Medline] [Order article via Infotrieve]
15. Viberti GC, Bending JJ. Early diabetic nephropathy: detection and prevention. Adv Nephrol. 1988;17:101-112.
16. Anderson S, Brenner BM. Therapeutic implications of converting-enzyme inhibitors in renal disease. Am J Kidney Dis. 1987;10(suppl 1):81-87.
17. Slataper R, Vicknair N, Sadler R, Bakris GL. Comparative effects of different antihypertensive treatments of progression on diabetic renal disease. Arch Intern Med. 1993;53:973-980.
18.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The
effect of angiotensin-converting-enzyme inhibition
on diabetic nephropathy. N Engl J
Med. 1993;329:1456-1462.
19.
Bakris GL.
Angiotensin-converting enzyme inhibitors
and progression of diabetic nephropathy. Ann
Intern Med. 1993;118:643-644.
20.
Viberti GC, Mogensen CE, Groop LC, Pauls JF.
Effect of captopril on progression to clinical proteinuria in patients
with insulin-dependent diabetes mellitus and
microalbuminuria. JAMA. 1994;271:275-279.
21.
Maki DD, Ma JZ, Louis TA, Kasiske BL.
Long-term effects of antihypertensive agents on proteinuria and
renal function. Arch Intern Med. 1995;155:1073-1080.
22.
Epstein M. Calcium antagonists and
diabetic nephropathy. Arch Intern Med. 1991;151:2361-2364.
23. Bakris GL. Calcium abnormalities and the diabetic, hypertensive patient: Implications for renal preservation. In: Epstein M, ed. Calcium Antagonists in Clinical Medicine. Philadelphia, Pa: Hanley & Belfus; 1992:367-389.
24. Anderson S, Rennke HG, Brenner BM. Nifedipine versus fosinopril in uninephrectomized diabetic rats. Kidney Int. 1992;41:891-897. [Medline] [Order article via Infotrieve]
25.
Jyothirmayi GN, Reddi AS. Effect of diltiazem on
glomerular heparan sulfate and albuminuria in
diabetic rats. Hypertension. 1993;21:795-802.
26. Kanwar YS, Liu ZZ, Kashihara N, Wallner EI. Current status of the structural and functional basis of glomerular filtration and proteinuria. Semin Nephrol. 1991;11:390-413. [Medline] [Order article via Infotrieve]
27. Rosenzweig LJ, Kanwar YS. Removal of sulfated (heparan sulfate) or nonsulfated (hyaluronic acid) glycosaminoglycans results in increased permeability of glomerular basement membrane to 125I bovine serum albumin. Lab Invest. 1982;47:177-184. [Medline] [Order article via Infotrieve]
28. Van Den Born J, Van Den Heuvel LPWJ, Bakker MAH, Veerkamp JH, Assmann KJM, Berden JHM. A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats. Kidney Int. 1992;41:115-123. [Medline] [Order article via Infotrieve]
29. Parthasarathy N, Spiro RG. Effect of diabetes on the glycosaminoglycan component of the human glomerular basement membrane. Diabetes. 1982;31:738-741. [Abstract]
30. Cohen MP, Surma ML. (35S)sulfate incorporation into glomerular basement membrane glycosaminoglycans is decreased in experimental diabetes. Lab Clin Med. 1981;98:715-722.
31. Brown DM, Klein DJ, Michael AF, Oegema TR. 35S-glycosaminoglycan and 35S-glucopeptide metabolism by diabetic glomeruli and aorta. Diabetes. 1982;31:418-425. [Abstract]
32.
Kanwar YS, Rosenzweig LJ, Linker A, Jakubowski
ML. Decreased de novo synthesis of glomerular
proteoglycans in diabetes: biochemical and
auto-radiographic evidence. Proc Natl
Acad Sci U S A. 1983;80:2272-2275.
33. Reddi AS. Glomerular and urinary glycosaminoglycans in diabetic rats. Clin Chim Acta. 1990;189:211-220. [Medline] [Order article via Infotrieve]
34. Rohrbach DH, Hassell JR, Kleinman HK, Martin GR. Alterations in the basement membrane (heparan sulfate) proteoglycan in diabetic mice. Diabetes. 1982;31:185-188. [Abstract]
35. Reddi AS. Prevention of albuminuria by captopril in diabetic rats. Gen Pharmacol. 1991;22:323-328. [Medline] [Order article via Infotrieve]
36. Reddi AS, Ramamurthi R, Miller M, Dhuper S, Lasker N. Enalapril improves albuminuria by preventing glomerular loss of heparan sulfate in diabetic rats. Biochem Med Metab Biol. 1991;45:119-131. [Medline] [Order article via Infotrieve]
37. Brodows RG, Nichols D, Shaker G, Kubasik NP. Evaluation of a new radioimmunoassay for urinary albumin. Diabetes Care. 1986;9:189-193. [Abstract]
38.
Weibel ER, Gomez DM. A principle for counting
tissue structures on random sections. J Appl
Physiol. 1962;17:343-348.
39. Meyer TW. Mechanisms of proteinuria in diabetic renal disease. Semin Nephrol. 1990;10:194-202. [Medline] [Order article via Infotrieve]
40. Myers BD, Nelson RG, Tan M, Beck GJ, Bennett PH, Knowler WC, Blouch K, Mitch WE. Progression of overt nephropathy in non-insulin-dependent diabetes. Kidney Int. 1995;47:1781-1789.[Medline] [Order article via Infotrieve]
41. Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes. Kidney Int. 1981;19:410-415. [Medline] [Order article via Infotrieve]
42. Zatz R, Brenner BM. Pathogenesis of diabetic microangiopathy: the hemodynamic view. Am J Med. 1986;80:443-453. [Medline] [Order article via Infotrieve]
43. Brown SA, Walton CL, Crawford P, Bakris GL. Long-term effects of antihypertensive regimens on renal hemodynamics and proteinuria. Kidney Int. 1993;43:1210-1218. [Medline] [Order article via Infotrieve]
44. Riser BL, Cortes P, Zhao X, Bernstein J, Dumler F, Narins RG. Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest. 1992;90:1932-1943.
45.
Shaklai N, Garlick RL, Bunn HF. Nonenzymatic
glycosylation of human serum albumin alters its conformation
and function. J Biol Chem. 1984;259:3812-3817.
46. Ghiggeri GM, Candiano G, Delfino G, Bianchini F, Queirolo C. Glucosyl albumin and diabetic microalbuminuria: demonstration of an altered renal handling. Kidney Int. 1984;25:565-570. [Medline] [Order article via Infotrieve]
47.
Erley CM, Haefele U, Heyne N, Braun N, Risler T.
Microalbuminuria in essential hypertension: reduction
by different antihypertensive drugs.
Hypertension. 1993;21:810-815.
48. Feher MD. Doxazosin therapy in the treatment of diabetic hypertension. Am Heart J. 1991;121:1291-1301.
49. Lehtonen A. Doxazosin effects on insulin and glucose in hypertensive patients. Am Heart J. 1991;121:1307-1311. [Medline] [Order article via Infotrieve]
50. Lithell HOL. Effect of antihypertensive drugs on insulin, glucose and lipid metabolism. Diabetes Care. 1991;14:203-209. [Abstract]
51. Kageyama S, Yamamoto J, Minura A, Sakurai, T, Ishibashi K, Aihara K, Taniguchi I, Ito K, Isogai Y. Doxazosin improves insulin sensitivity in hypertensive patients. Clin Ther. 1993;15:829-837. [Medline] [Order article via Infotrieve]
52.
Giordano M, Matsuda M, Sanders L, Canessa ML, De Fronzo
RA. Effects of angiotensin-converting enzyme
inhibitors, Ca2+ channel
antagonists and -adrenergic blockers on glucose and
lipid metabolism in NIDDM patients with
hypertension. Diabetes. 1995;44:665-671.[Abstract]
53. Huupponen R, Lehtonen A, Vahatalo M. Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients. Eur J Clin Pharmacol. 1992;43:365-368. [Medline] [Order article via Infotrieve]
54. Maheux P, Facchini F, Jeppesen J, Greenfield MS, Clinkingbeard C, Chen YDI, Reaven GM. Changes in glucose, insulin, lipid, lipoprotein, and apoprotein concentrations and insulin action in doxazosin-treated patients with hypertension: comparison between nondiabetic individuals and patients with non-insulin-dependent diabetes mellitus. Am J Hypertens. 1994;7:416-424. [Medline] [Order article via Infotrieve]
55. Steffes MW, Brown DM, Basgen JM, Mauer SM. Amelioration of mesangial volume and surface alterations following islet transplantation in diabetic rats. Diabetes. 1980;29:509-515. [Medline] [Order article via Infotrieve]
56. Anderson S, Rennke HG, Garcia DL, Brenner BM. Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int. 1989;36:526-536. [Medline] [Order article via Infotrieve]
57. Gaber L, Walton C, Brown S, Bakris G. Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs. Kidney Int. 1994;46;161-169.
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