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)

We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide in chronically hypertensive dogs. 755 24

The protective effects of phosphoramidon, a dual inhibitor of endothelin-converting enzyme and neutral endopeptidase (E.C. 24.11), on renal function in ischemic acute renal failure were investigated in anesthetized rats. Intravenous infusion of phosphoramidon (0.03 and 0.1 mg/kg per min) significantly suppressed tubular sodium wasting (measured by fractional excretion of sodium) and proteinuria in the postischemic kidney without modifying functional parameters in the contralateral normal kidney. Phosphoramidon (0.1 mg/kg/min) was associated with increased glomerular filtration in the ischemic kidney. In comparison, SCH 42354, a highly selective inhibitor of neutral endopeptidase at 0.3 mg/kg/min, did not inhibit endothelin-converting enzyme or afford renal protection. The data suggest that the protective action of phosphoramidon against ischemic acute renal failure is most likely mediated by inhibition of endothelin formation.
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PMID:Attenuation of ischemic acute renal failure by phosphoramidon in rats. 841 69

The purpose of these studies was to compare the effects of CGS 30440 (CGS), a dual angiotensin-converting enzyme inhibitor (ACEI)/neutral endopeptidase inhibitor (NEPI) to benazepril (BZ), an ACEI, in a model of five-sixths nephrectomy. The doses of BZ and CGS 30440 tested were 6.5 micromol/kg/day and 2.2 micromol/kg/day. Drugs or vehicle (V) were administered subcutaneously for 6 weeks with dosing initiated 1 week after renal mass reduction. At 6 weeks of receiving drug (7 weeks after five-sixths nephrectomy), CGS/6.5 and BZ/6.5 and CGS/2.2 maintained systolic blood pressures (SBP) at presurgical values. BZ/2.2 did not reduce SBP and was similar to the V group. Urinary protein excretion increased >10-fold in the V-treated group. BZ, at either dose, reduced the proteinuria slightly. CGS/6.5 and CGS/2.2 caused significant (p < 0.05) reductions in proteinuria. Creatinine clearance (Cr(cl)), was reduced by 82% in V, 65 and 61% in the CGS/6.5 and CGS/2.2 groups, and by 69 and 74% in the BZ/6.5 and BZ/2.2 groups, respectively. Both CGS treatments improved the fractional excretion of Na+ (%FE(Na)) significantly from the BZ and V groups. The %FE(Na) for BZ at either dose did not differ from that of V. Elevated urinary cyclic guanosine monophosphate (cGMP), an indicator suggesting increased intrarenal levels of atrial natriuretic peptide (ANP), was observed only in the CGS groups. Histologic examination indicated that BZ/6.5 reduced glomerular sclerosis and the extent of tubular dilation, whereas BZ/2.2 had little effect. CGS, especially at the high dose, virtually normalized the glomerular and tubular pathology. Compared with BZ, CGS 30440 treatment further diminished tubular dilation and proteinaceous cast formation. These tubular effects are consistent with some of the renal actions of ANP. The results from these studies indicate that CGS 30440, a combined ACEI/NEPI, conferred a greater renal protective effect than did ACE inhibition alone.
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PMID:Protective effects of CGS 30440, a combined angiotensin-converting enzyme inhibitor and neutral endopeptidase inhibitor, in a model of chronic renal failure. 967 26

These studies examined the interactions of neutral endopeptidase (NEP), endothelin-1 (ET-1), and nitric oxide (NO) in deoxycorticosterone acetate (DOCA)-induced hypertension. Male Sprague-Dawley rats (n = 35) were uninephrectomized (UNx) or uninephrectomized and treated with DOCA (25 mg pellet implanted subcutaneously). Candoxatril (30 mg/kg day(-1)), a NEP inhibitor, was given orally for 3 weeks in UNx or DOCA rats. Sham nephrectomized rats (SHAM) served as controls. Except SHAM, all other groups received 1% NaCl in drinking water ad libitum. Measurements were taken of systolic blood pressure (SBP), left ventricle (LV), and aortic weight (AW), plasma ET-1, and urinary excretion of nitrite and Na+. Whole body vascular hypertrophy and morphometric analysis of histological sections of the heart were also determined. In DOCA rats, SBP increased from 113 +/- 5 to 170 +/- 5 mmHg without significant changes in body weight (BW). Candoxatril reduced the increase in SBP to 135 +/- 9 mmHg (P < 0.05), abolished the increased LV wall thickness (P < 0.05), and increased the reduced LV lumen diameter (P < 0.05) in DOCA-salt rats. Candoxatril also reduced plasma ET-1 by 88 +/- 9% and 89 +/- 17% (P < 0.05) in UNx and DOCA rats, respectively, and elicited increases in urinary excretion of nitrite. These effects were accompanied by a marked increase in urinary excretion of Na+ (U(Na)V) (P < 0.05) and a blunting of the proteinuria (32 +/- 5%; P < 0.05) in DOCA rats. We conclude that endopeptidase inhibition in DOCA-salt hypertension reduced the increase in blood pressure and the attendant tissue hypertrophy and renal injury. These effects suggest a correlation between endopeptidase-related reduction in ET-1 production and protection in DOCA-salt hypertension.
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PMID:Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection. 1294 Apr 71

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.
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PMID:Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats. 1456 1

1. Vasopeptidase inhibition (i.e., the simultaneous inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase) can ameliorate diabetic nephropathy. We investigated whether this nephroprotection is mediated by the bradykinin B2 receptor. 2. In all, 43 obese Zucker diabetic fatty (ZDF/Gmi-fa/fa) rats aged 21 weeks were separated into four groups and treated for 26 weeks with either placebo, the bradykinin B2 receptor antagonist icatibant (500 microg kg(-1) day(-1) s.c. infusion), the vasopeptidase inhibitor AVE7688 (45 mg kg(-1) day(-1) in chow), or AVE7688 plus icatibant. Nephropathy was assessed as albuminuria at age 31 and 39 weeks, and by histopathologic scoring at the end of the treatment period. 3. All animals had established diabetes mellitus (blood glucose >20 mmol l(-1)) and marked albuminuria at baseline. Blood glucose was not influenced by any treatment. Icatibant alone did not influence albuminuria (8.6+/-1.6 vs placebo 9.5+/-1.3 mg kg(-1) h(-1)). AVE7688 reduced albuminuria at week 31 markedly to 1.1+/-0.1 mg kg(-1) h(-1) and reduced glomerular and tubulo-interstitial kidney damage at week 47. In the AVE7688 plus icatibant group, proteinuria was significantly higher than in the AVE7688 only group (2.0+/-0.6 mg kg(-1) h(-1)), but still reduced compared to placebo. In addition, icatibant partly antagonized the tubulo-interstitial protection mediated by AVE7688. 4. We conclude that vasopeptidase inhibition provides nephroprotection in rats with type II diabetic nephropathy, which is partly mediated by bradykinin B2 receptor activation.
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PMID:Nephroprotection in Zucker diabetic fatty rats by vasopeptidase inhibition is partly bradykinin B2 receptor dependent. 1528 89

Membranous nephropathy (MN), the most common cause of idiopathic nephrotic syndrome in white adults, is characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane. In Heymann nephritis, the rat experimental model for MN, megalin--the target antigen of the nephritogenic antibodies--is expressed on the surface of podocytes, where immune complexes are formed, leading to complement activation and nephrotic-range proteinuria. However, megalin cannot be held responsible for human MN because it has not been found in human podocytes or detected in subepithelial immune deposits in patients with MN. Several potential antigens have been identified in so-called secondary forms of MN, but there is no real proof that these antigens are pathogenic. In a subgroup of infants with antenatal MN, neutral endopeptidase (NEP) has been identified as the first protein target on human podocytes of nephritogenic antibodies. The infants' mothers became immunized during pregnancy against NEP expressed on syncytiotrophoblastic cells because they were NEP deficient as a result of truncating mutations in the MME gene. Severity of neonatal renal disease was determined by the mothers' IgG response that led to the formation of the membrane attack complex of complement in the subepithelial deposits. Alloimmunization against NEP is a novel pathomechanism of MN that might also account for some cases of MN after renal or bone marrow transplantation. Other types of alloimmunization should be investigated in MN but also in other renal and nonrenal diseases, particularly those that affect the pediatric age.
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PMID:Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization. 1580 Jan 20

Recent results indicate that intrinsic glomerular cells (podocytes, mesangial and endothelial cells) are active participants in the inflammatory process in the glomerulus. Particular attention is drawn to podocyte injury in glomerulonephritis. Podocytes are end-differentiated cells which have lost their proliferation abilities and can only compensate by hypertrophy. The inability to proliferate is the cost which a podocyte must pay for the development of highly specialized structures and ability to adhere to the glomerular basement membrane. Collapsing focal-segmental glomerulosclerosis is a condition in which podocytes proliferate, but this process is associated with loss of their maturity markers as well as with abnormalities in the expressions of cell cycle proteins. Dysfunction of slit diaphragms is an important element in the pathogenesis of glomerulopathies with marked proteinuria. Recent studies also underline the importance of neprilysin in the pathogenesis of glomerulonephritis. This is the first podocytic antigen which has been shown to induce human membranous glomerulonephritis.
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PMID:[The role of podocytes in normal glomerular function and in the pathogenesis of glomerulonephritis. Part II. Phenotypic and functional changes of podocytes in glomerulonephritis]. 1670 25

Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosterone-system and/or vasoactive peptides that are metabolized by neutral endopeptidase (NEP). The renoprotective effect of angiotensin-converting enzyme inhibition (ACEi) as well as combined ACE/NEP inhibition with a vasopeptidase inhibitor (VPI) was investigated in the same model to clarify the underlying mechanism. At week 17 after sequential induction of unilateral nephrectomy and myocardial infarction, treatment with lisinopril (ACEi), AVE7688 (VPI), or vehicle was initiated for 6 wk. Proteinuria and systolic BP (SBP) were evaluated weekly. Renal damage was assessed primarily by proteinuria, interstitial alpha-smooth muscle actin (alpha-SMA) staining, and the incidence of focal glomerulosclerosis (FGS). At start of treatment, proteinuria had increased progressively to 167 +/- 20 mg/d in the entire cohort (n = 42). Both ACEi and VPI provided a similar reduction in proteinuria, alpha-SMA, and FGS compared with vehicle at week 23 (proteinuria 76 +/- 6 versus 77 +/- 4%; alpha-SMA 60 +/- 6 versus 77 +/- 3%; FGS 52 +/- 14 versus 61 +/- 10%). Similar reductions in systolic BP were observed in both ACEi- and VPI-treated groups (33 +/- 3 and 37 +/- 2%, respectively). Compared with ACEi, VPI-treated rats displayed a significantly larger reduction of plasma (41 +/- 5 versus 61 +/- 4%) and renal (53 +/- 6 versus 74 +/- 4%) ACE activity. It is concluded that both ACEi and VPI intervention prevent renal damage in a rat model of cardiorenal interaction. VPI treatment seemed to provide no additional renoprotection compared with sole ACEi after 6 wk of treatment in this model, despite a more pronounced ACE-inhibiting effect of VPI.
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PMID:Renal damage after myocardial infarction is prevented by renin-angiotensin-aldosterone-system intervention. 1700 35

Membranous nephropathy, a disease characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, is the most common cause of idiopathic nephrotic syndrome in white adults. In the rat model of Heymann nephritis, the target antigen of antibodies is megalin, a multiligand receptor expressed at the podocyte cell surface. This review summarizes key findings provided by this experimental model and by our discovery of neutral endopeptidase being the alloantigen involved in neonatal cases of membranous nephropathy. We discuss the role of alloimmunization as a new mechanism of renal disease and the approach that we use to identify new podocyte antigens. We also summarize current knowledge on the mechanism of proteinuria, with special emphasis on the role of complement. In conclusion, substantial progresses have been made in understanding molecular mechanisms of membranous nephropathy, which should lead to novel therapeutic approaches.
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PMID:Target antigens and nephritogenic antibodies in membranous nephropathy: of rats and men. 1789 86


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