Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.
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PMID:Comparison between the effects of amlodipine and lisinopril on proteinuria in nondiabetic renal failure: a double-blind, randomized prospective study. 975 92

Previous studies showed a renoprotective effect of l-arginine in experimental uremia. Whether this was caused by an increased nitric oxide (NO) release or depended on l-arginine per se is not clear. Here, we evaluated whether chronic administration of an NO donor, molsidomine, controlled systemic blood pressure and renal disease progression and prolonged survival in rats with renal mass reduction (RMR). Rats with RMR received the following daily in the drinking water: group 1 (n = 21), no specific therapy (vehicle); group 2 (n = 12), molsidomine, 120 mg/L; group 3 (n = 9), lisinopril, 25 mg/L; and group 4 (n = 12), reserpine, 5 mg/L, hydralazine, 80 mg/L, and hydrochlorothiazide, 25 mg/L, from day 21 after surgery, when rats had hypertension and proteinuria, until the death of the vehicle-treated rats. Molsidomine normalized systemic hypertension, only partially reduced proteinuria and serum creatinine levels, but significantly prolonged animal survival, particularly in the early stage of the disease. Lisinopril at a similar systemic blood pressure was even better than molsidomine in limiting proteinuria, preserving renal function, and prolonging survival, but triple therapy, despite being effective on blood pressure, offered no renoprotection or prolonged survival. Endothelin-1 (ET-1) levels, formed in excessive amounts by the kidneys of these animals, were reduced by molsidomine and lisinopril, but not by triple therapy. The prolongation of survival by NO donor could be attributed to its effect of reducing ET levels, which in turn may limit the smooth muscle cell proliferation and matrix accumulation responsible for organ and, especially, myocardial fibrosis in uremia.
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PMID:Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model. 1019 19

Experimental data consistently indicate that renal disease progression is fully prevented in proteinuric glomerulopathies by long-enough angiotensin-converting enzyme (ACE) inhibition therapy. Whether regression of established proteinuria to normal can be achieved is, however, ill defined. The current study was designed with the aim to clarify whether ACE inhibition may induce regression of established proteinuria and renal structural damage in MWF rats, a genetic model of progressive proteinuria and renal injury. Animals treated with the ACE inhibitor lisinopril from 20 weeks of age (time when proteinuria is already important) and age-matched untreated rats were followed for 10 weeks. ACE inhibition normalized systolic blood pressure and progressively reduced proteinuria (from 172 +/- 79 to 81 +/- 23 mg/24 hours). In these animals, a highly significant correlation was obtained between baseline proteinuria and antiproteinuric response. At variance in untreated rats, proteinuria showed a marked increase in the 10-week follow-up period (from 165 +/- 57 to 325 +/- 86 mg/24 hours). Lisinopril prevented the progression of renal damage, as documented by a significantly lower incidence of glomeruli affected by sclerotic lesions (P < 0.01) than in untreated animals after the 10-week study period. Kidney tissue damage was comparable in lisinopril-treated rats and in untreated animals at 20 weeks of age, indicating that structural changes were arrested by the treatment. Thus, in proteinuric MWF rats, late-onset ACE inhibition normalized blood pressure, effectively and progressively restored high protein excretion rate toward normal values, and arrested progression of tissue damage.
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PMID:ACE inhibition induces regression of proteinuria and halts progression of renal damage in a genetic model of progressive nephropathy. 1051 41

Nephrosis induced by doxorubicin (adriamycin) is an experimental model of glomerulosclerosis with relative stable proteinuria which is commonly used for pharmacological intervention studies. It is induced by a single or a double dose of doxorubicin, with doses that vary considerably among investigators from 2 to 7.5 mg/kg. Intervention studies with ACE-inhibitors in this model have provided conflicting results. We hypothesized that these discrepancies might be due to different properties of the doxorubicin model, related to the dose of doxorubicin used to induce proteinuria. We tested this hypothesis by inducing doxorubicin nephrosis with 1, 2 and 3 mg/kg, and evaluating the response to intervention with lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg/ kg dose resulted in a proteinuria of 684+/-215 mg/24 h and 736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment with lisinopril 2 mg/kg/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in the 2-mg/kg doxorubicin group, whereas in the 3-mg/kg doxorubicin group, proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control rats, proteinuria remained stable. Renal damage developed in both time control groups, with a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/-41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lower glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05), whereas the 3-mg/kg group showed no significant reduction (56+/-29, NS). In conclusion, the dose of doxorubicin used to induce nephrosis is an important determinant not only of the severity of the ensuring renal damage, but also of the response to intervention by ACE-inhibition. These findings have an impact on the interpretation of intervention studies in this model.
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PMID:Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis. 1059 77

The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens- (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.
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PMID:Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats. 1070 71

Mononuclear cells accumulate in the renal interstitium and contribute to renal injury in proteinuric nephropathies. Angiotensin-converting enzyme (ACE) inhibitors reduce protein trafficking and also lessen renal structural and functional damage. Many proinflammatory genes, including monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes and T lymphocytes, are transcriptionally regulated by nuclear factor-kappa B (NF-kB). We aimed to study NF-kB activation and MCP-1 expression over time in two models of progressive proteinuric nephropathies (5/6 nephrectomy and passive Heymann nephritis [PHN]) and evaluate the effect of antiproteinuric therapy with an ACE inhibitor on these factors. In both models, increased urinary protein excretion over time was associated with a remarkable increase in NF-kB activity, which was almost completely suppressed by reducing proteinuria with lisinopril. NF-kB activation was paralleled by upregulation of MCP-1 messenger RNA and interstitial accumulation of ED-1-positive monocytes/macrophages and CD8-positive T cells. Lisinopril inhibited MCP-1 upregulation and limited interstitial inflammation. In a group of PHN rats with advanced disease and severe proteinuria, a dose of lisinopril high enough to inhibit renal ACE activity failed to reduce proteinuria and also did not limit NF-kB activation, which was sustained over time, along with MCP-1 gene overexpression and interstitial inflammation. These data suggest that NF-kB is activated in the presence of increased protein traffic, enhancing the nuclear transcription of the MCP-1 gene with potent chemotactic and inflammatory properties. This mechanism may help explain the long-term renal toxicity of filtered proteins.
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PMID:Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation. 1109 48

Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.
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PMID:Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. 1131 52

Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.
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PMID:Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation. 1132 51

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), proteinuria (6.1+/-1.5 g/24 h) and biopsy proven CR. Lisinopril (10-40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8+/-2.2 to 3.4+/-1.9 g/24 h, p<0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5+/-0.05 to 0.3+/-0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.
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PMID:Renal tubular peptide catabolism in chronic vascular rejection. 1149 66

The present study was performed to clarify the mechanism underlying the beneficial effects of lisinopril on chronic glomerulonephritis. Chronic glomerulonephritis was induced by a single injection of E30 monoclonal antibody (E30) recognizing Thy-1.1 antigen to unilaterally nephrectomized rats. E30 injection resulted in persistent massive proteinuria with a decrease in anionic charge sites on the glomerular basement membrane (GBM) at 8 weeks. Also, renal tissue from rats treated with E30 showed typical glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril exerted a potent antiproteinuric effect and suppressed the progression of both glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril recovered the reduced number of anionic charge sites on GBM, accounting for the positive action against massive proteinuria. Immunostaining for desmin revealed that lisinopril treatment prevented the injury of glomerular epithelial cells (GECs) occurring in the chronic nephritic stage. Also, the level of gene expression of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1) in the renal cortex were reduced, suggesting that lisinopril improved extracellular matrix (ECM) metabolism. These results indicated that proteinuria in Thy-1.1 antibody-induced chronic nephritis is associated with a decrease in anionic charge sites on GBM, and that the antiproteinuric effect of lisinopril is attributable to protection against GEC damage. Suppression of TGF-beta and PAI-1 expression contributed to the preventive effect of lisinopril on ECM deposition in renal tissue.
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PMID:Mechanisms underlying the ameliorative property of lisinopril in progressive mesangioproliferative nephritis. 1213 78


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