Enalapril improves albuminuria by preventing glomerular loss of heparan sulfate in diabetic rats

Reddi, Alluru S.; Ramamurthi, R.; Miller, Marilyn; Dhuper, Sonal; Lasker, Norman

doi:10.1016/0885-4505(91)90014-c

Cited by 64 publications

(39 citation statements)

References 38 publications

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“…AngII also reduces HSPG expression in human podocytes, as could be demonstrated by a recent study from our group (13). In line with these in vitro findings are in vivo data showing that the ACE inhibitor enalapril improves albuminuria by preventing glomerular loss of HS in diabetic rats (14). Therefore, the antiproteinuric effect of ACE inhibition in DN may be explained at least partially by structural effects on the glomerular basement membrane (GBM); i.e., qualitative and quantitative preservation of HSPG improving glomerular permselectivity.…”

supporting

confidence: 81%

Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

Benck

Haeckel

Clorius

et al. 2007

Clinical Journal of the American Society of Nephrology

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Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with 99m Tc-DTPA and 131 Ihippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.

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supporting

confidence: 81%

Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

Benck

Haeckel

Clorius

et al. 2007

Clinical Journal of the American Society of Nephrology

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“…The actions of ACEI and sulodexide overlap in some ways, but there are differences that may explain sulodexide's additive effects to those of ACE inhibition alone. For example, although sulodexide diminishes the hyperglycemia-induced overexpression of TGF-␤1, the mechanism of TGF-␤1 modulation by ACEI is most likely different (35,38).…”

Section: Discussionmentioning

confidence: 99%

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

Gambaro

Kinalska²,

Oksa³

et al. 2002

Journal of the American Society of Nephrology

172

126

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Abstract. Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensinconverting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine Յ150 mol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 Ϯ 0.18 at T0 to 3.98 Ϯ 0.11 at T4 (P Ͻ 0.05), which was maintained till T8 (4.11 Ϯ 0.13; P Ͻ 0.05 versus T0). Moreover, the sulodexideinduced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P ϭ 0.03; 49% [30 to 63%], P ϭ 0.0001; and 74% [64 to 81%], P ϭ 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P ϭ 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro-or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.Diabetes is the most common cause of end-stage renal disease (ESRD) in Western countries. In the United States, diabetes currently accounts for 44% of all new cases of ESRD (1). Despite advances in clinical care, the incidence of diabetes mellitus type 2 (DM2)-related cases of ESRD is rapidly increasing (2), and survival of DM-related ESRD patients on dialysis is markedly low (3,4).The anatomic hallmarks of diabetic nephropathy (DN) include thickening of the glomerular basement membrane (GBM) and mesangial expansion with hyalinosis both in the mesangium and capillary lumen. These lesions lead to glomerular fibrosis, which progressiv...

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“…This is consistent with our prediction if the same membrane change that lowers the glomerular permeability to albumin (fraction of large pores) also increases the filtration capacity (pore density). Antihypertensive treatment with an angiotensin converting enzyme inhibitor has been shown to improve both size and charge selective properties [32,33].…”

Section: Discussionmentioning

confidence: 99%

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

et al. 1994

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Summmr/ Diabetic nephropathy is the main cause of increased mortality and morbidity in IDDM patients. The effect of antihypertensive treatment on the progression of the nephropathy is highly variable. The aim of this study was to evaluate putative predictors of the progression in diabetic nephropathy during long-term antihypertensive treatment. Eighteen hypertensive IDDM patients with diabetic nephropathy, who had not been treated previously, were followed during 3 years of treatment with captopril and frusemide or bendrofluazide. Glomerular filtration rate, arterial blood pressure, albuminuria and adjusted albuminuria were used as putative predictors of rate of decline in glomerular filtration. Fall rate in glomerular filtration rate was 4.6 (4.0) ml. min-1 .year 1 (mean (SD)) during treatment. Relative change in albuminuria (ratio of first year of treatment/baseline) and albuminuria during first year of treatment were significantly correlated to fall rate in glomerular filtration rate during 3 years of treatment (r --0.73, p < 0.001) and (r = 0.60, p < 0.01), respectively. Arterial blood pressure and glomerular filtration rate measured at baseline, during first year of treatment or relative changes in these variables did not correlate with fall rate in glomerular filtration rate during 3 years of treatment. Haemoglobin AI:, serum-cholesterol, protein intake and sodium excretion remained unchanged during treatment, and were not correlated with loss of kidney function. Reduction in albuminuria during captopril treatment predicts an attenuated rate of decline in glomerular filtration rate in early diabetic nephropathy (glomerular filtration rate > 70 ml. rain -1-1.73 m-Z). The finding suggests a clinical application in monitoring the efficacy of antihypertensive treatment in early diabetic nephropathy. [Diabetologia (1994) 37: 511-516] Key words Diabetic nephropathy, albuminuria, antihypertensive treatment, glomerular filtration rate.Diabetic nephropathy develops in 30-40 % of IDDM patients [1,2], and nephropathy is the main cause of increased morbidity and mortality in these patients [1]. Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, a relentless decline in glomerular filtration rate, and raised arterial blood pressure [3]. Human and animal studies have demonstrated a correlation between elevation in arterial Received: 21 September 1993 and in revised form: 3 December 1993Corresponding author: Dr. R Rossing~ Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, DenmarkAbbreviations: IDDM, Insulin-dependent diabetes mellitus blood pressure and development and progression of diabetic glomerulopathy [4][5][6][7][8][9][10]. Several studies [11][12][13][14][15][16][17] have demonstrated that the rate of decline in glomerular filtration rate can be reduced by antihypertensive treatment. However the beneficial effect of antihypertensive treatment on the progression of the diabetic nephropathy is highly variable. From a clinical point of view, identification of predic...

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Enalapril improves albuminuria by preventing glomerular loss of heparan sulfate in diabetic rats

Cited by 64 publications

References 38 publications

Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

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