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)

Albuminuria (UAlbV) can be reduced by converting-enzyme inhibitors (CEI), but the hormonal mechanism responsible for this effect has not previously been defined. Since CEI increase kinin activity as well as reduce angiotensin II (ANG II) activity, experiments were performed to determine the effect of isolated alterations in kinin and ANG II metabolism on UAlbV in rats with passive Heymann pephritis. Phosphoramidon was used to potentiate kinin activity without altering ANG II synthesis. Aprotinin was utilized in combination with the CEI, enalapril, to prevent the increase in kinin activity caused by CEI. UAlbV and the fractional renal clearance of albumin (FCAlb) decreased significantly after either phosphoramidon or enalapril, although only enalapril reduced blood pressure. Glomerular filtration rate (GFR) was not affected by either drug. Phosphoramidon did not affect plasma renin activity (PRA) or the pressor response to angiotensin I (ANG I), indicating that ANG II synthesis was not altered. Aprotinin prevented the reduction in UAlbV and FCAlb produced by CEI but not the hypotension, elevated PRA, or ANG I pressor blockade produced by CEI. Aprotinin alone had no effect on UAlbV, GFR, PRA, or blood pressure. UAlbV can be reduced by increasing kinin activity by a mechanism that is not dependent on suppression of ANG II activity or reduction in GFR or blood pressure. CEI may reduce proteinuria as a result of their action on the kallikrein-kinin system rather than on the renin-angiotensin system.
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PMID:Effects of modulation of renal kallikrein-kinin system in the nephrotic syndrome. 169 47

In vitro release of renin, angiotensinogen and aldosterone was studied in control (CT) and nephrotic rats. Nephrotic syndrome (NS) was induced by a single injection of puromycin aminonucleoside (PA). The in vitro systems used were: renal cortical slices (RCS), liver slices (LS) and adrenal glands, all incubated in Krebs-Ringer buffer. Renal renin content (RRC) and isoproterenol-induced renin secretion (RS) also were studied. RS, RRC and angiotensinogen release were measured indirectly by radioimmunoassay (RIA) of angiotensin I (ANG I); aldosterone was estimated by direct RIA. Basal RS was not modified in NS: 385 +/- 196 (CT) vs 344 +/- 149 ng ANG I/mg protein/h (NS), p greater than 0.05. Isoproterenol increased RS significantly in both CT and NS groups: 535 +/- (CT) and 685 +/- 231 ng ANG I/mg protein/h (NS) (p less than 0.05 vs. basal RS). RRC was similar in both groups: 2.17 +/- 0.62 (CT) vs 2.05 +/- 0.49 micrograms ANG I/mg protein/h (NS), p greater than 0.05. Angiotensinogen release from LS increased in nephrotic rats from 10 +/- 3.2 (CT) to 12 +/- 1.9 pmoles angiotensinogen I/mg tissue/2h (NS), p less than 0.05. Aldosterone release increased markedly from adrenal glands of rats with NS (1649 +/- 1111 pg aldosterone/mg tissue/h) with respect to control rats (257 +/- 85), p less than 0.05 In vitro studies were performed six days after PA-injection, when nephrotic rats had ascitis, edema, proteinuria, hypoproteinemia, hypercholesterolemia, hypertriglyceridemia, low sodium and aldosterone excretion, low levels of plasma angiotensinogen and high levels of plasma renin and aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathophysiology of experimental nephrotic syndrome induced by puromycin aminonucleoside in rats. II. In vitro release of renin, angiotensinogen and aldosterone. 226 44

It has been suggested that angiotensin II (ANG II) activation after renal ablation contributes to the altered glomerular dynamics and proteinuria that characterizes this model of chronic renal failure. In the present study, male Munich-Wistar rats underwent 75% renal ablation (Nx group). Two weeks later, micropuncture studies were performed in sham-operated rats (sham group) and Nx group rats during intravenous infusion of either a vehicle or two ANG II inhibitors, namely [Sar1, Ala8]ANG II or MK-421 administered at a rate of 0.3 and 1 mg.kg body wt-1.h-1, respectively. Acute ANG II inhibition in sham group had no effect on mean arterial pressure (MAP), glomerular dynamics, or proteinuria. In contrast, in Nx group ANG II inhibition lessened glomerular hypertension (from 64.7 +/- 1.0 to 55.4 +/- 1.7 mmHg, P less than 0.0001) the result of postglomerular vasodilation (P less than 0.01), normalized the glomerular ultrafiltration coefficient (from 0.038 +/- 0.002 to 0.005 +/- 0.002 nl.s-1.mmHg-1, P less than 0.0001), and attenuated proteinuria (from 42.1 +/- 6.5 to 28.1 +/- 5.4 micrograms/min, P less than 0.01). MAP, single-nephron GFR and plasma flow were unaffected. These results suggest that ANG II activity is enhanced in nephrectomy, contributing in a major way to altered glomerular dynamics and proteinuria.
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PMID:Angiotensin II control of the renal microcirculation in rats with reduced renal mass. 230 95

Angiotensin II (ANG II) infusion has been reported to impair barrier size selectivity and exacerbate proteinuria in the rat. To examine whether this is also true of humans, we infused a pressor dose of ANG II into seven healthy controls and seven nephrotic patients. A prompt depression of glomerular filtration rate (GFR) and renal plasma flow was observed in each group (P less than 0.01). Surprisingly, the excretion rates of albumin (5.3 +/- 1.6 to 2.8 +/- 0.3 in controls and 4,791 +/- 1,244 to 3,833 +/- 800 micrograms/min in nephrotics) and immunoglobulin G (1.5 +/- 0.4 to 0.8 +/- 0.2 and 305 +/- 87 to 255 +/- 94 micrograms/min, respectively) fell significantly during ANG II infusion. Fractional clearances of dextrans of broad size distribution (radii 34-54 A) were uniformly elevated by ANG II infusion in controls but tended to decline in nephrotics. A heteroporous model of the glomerular capillary wall revealed ANG II to have a negligible effect on membrane-pore structure. However, the depressed GFR lowered the rate at which macromolecule-rich filtrate was formed through a subset of nondiscriminatory pores from 272 to 176 microliters/min in controls and from 394 to 334 microliters/min in nephrotics. We conclude that, in striking contrast to the rat, pressor ANG II infusion has little or no influence on barrier size selectivity in humans but exerts an antiproteinuric effect by lowering the filtered protein load.
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PMID:Effect of angiotensin II infusion on the human glomerular filtration barrier. 247 34

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.
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PMID:Role of angiotensin II in experimental membranous nephropathy. 283 20

Interruption of the renin-angiotensin-aldosterone system (RAAS) by converting enzyme inhibition or angiotensin II (ANG II) receptor antagonism dramatically reduces injury in the remnant kidney model. Furthermore, converting enzyme inhibition reduces proteinuria and slows the decline in renal function in clinical disease. Hemodynamic actions of ANG II in the kidney in conjunction with a more poorly defined effect of the RAAS on systemic hypertension have been posited as the major mechanisms for maintenance of elevated glomerular pressure. Reductions in glomerular pressure have been attributed, at least in part, to removal of intrarenal effects of ANG II. Growth and fibrotic actions of ANG II may also contribute to progressive renal injury and relief from them reduce injury. The participation of circulating aldosterone in the remnant kidney model has been recently raised. Hyperaldosteronism and adrenal hypertrophy attend the hypertension, proteinuria, and glomerulosclerosis of this model. Although the hemodynamic actions of aldosterone probably account for some of the adverse effects it has in this model, other direct cellular actions may participate in its renal, as well as cardiac and fibrotic consequences. Thus, the RAAS, working through both ANG II and aldosterone, contributes to chronic progressive renal injury.
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PMID:Role of the renin-angiotensin-aldosterone system in the progression of renal disease: a critical review. 931 11

Nephrotic syndrome is associated with resistance to the renal actions of atrial natriuretic peptide (ANP). We performed experiments in anesthetized, acutely nephrectomized rats 21-28 days after injection of adriamycin (7-8 mg/kg i.v.) or 9-14 days after injection of anti-Fx1A antiserum (5 ml/kg i.p.) (passive Heymann nephritis; PHN) to test whether extrarenal resistance also occurred. Proteinuria was significantly elevated in both models compared with controls before study. ANP infusion (1 microgram.kg-1.min-1) caused arterial pressure to decrease similarly in control rats, adriamycin-treated rats, and rats with PHN (by 8.2 +/- 1.0, 9.4 +/- 2.3, and 9.0 +/- 2.0%, respectively; all P < 0.05 vs. both baseline and vehicle-infused control rats). In control rats, hematocrit increased progressively to a maximal value 9.5 +/- 0.9% over baseline as a result of the infusion, an increase corresponding to a reduction in plasma volume of 16.1 +/- 0.9%. The ANP-induced increase in hematocrit was preserved in adriamycin-treated rats (9.2 +/- 1.3%) but was markedly blunted in rats with PHN (2.4 +/- 1.3%; P < 0.0001 vs. ANP infusion in control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate was significantly lower in rats with PHN compared with both control and adriamycin-treated rats. Infusion of a subpressor dose of angiotensin II (ANG II, 2.5 ng.kg-1.min-1) fully restored the ANP-induced increase in hematocrit in rats with PHN. This study demonstrates that 1) the hemoconcentrating and hypotensive actions of ANP are preserved in adriamycin-treated rats, 2) the effect of ANP on hematocrit and fluid distribution is blunted in rats with PHN while its hypotensive action is preserved, and 3) low-level ANG II infusion normalizes the hemoconcentrating effect of exogenously infused ANP in rats with PHN. Thus deficient ANG II generation in rats with PHN, but not adriamycin nephrosis, may contribute to extrarenal ANP resistance.
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PMID:Extrarenal resistance to atrial natriuretic peptide in rats with experimental nephrotic syndrome. 953 Feb 72

Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage. Despite evidence that angiotensin-converting enzyme (ACE) inhibitors improve glomerular size-selectivity, whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet. We studied 20 proteinuric patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of blood pressure, renal hemodynamics, and fractional clearance of neutral dextran of graded sizes were performed before and after 28 days of treatment. Both enalapril and irbesartan significantly reduced blood pressure over baseline. This reduction reached the maximum effect 4-6 h after drug administration but did not last for the entire 24-h period. Despite transient antihypertensive effect, proteinuria was effectively reduced by both treatments to comparable extents. Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules, but both effectively reduced transglomerular passage of large test macromolecules. Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution, but both importantly and comparably reduced the importance of a nonselective shunt pathway. These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins.
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PMID:ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy. 1007 Jan 70

Locally increased synthesis of angiotensin II (ANG II) in the kidney has been linked to glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial fibrosis observed in chronic renal failure after subtotal nephrectomy. This action of ANG II is thought to be mediated mainly by transforming growth factor-beta (TGF-beta), which stimulates the synthesis and decreases the degradation of extracellular matrix (ECM) components, including various collagen types and fibronectin. Some recent reports indicate that reduced ANG II activity diminishes TGF-beta overexpression, and in consequence renal injury. However, no studies in SNx models concerning the influence of ANG II on gene expression regulated by TGF-beta have so far been performed. Therefore, the present study has been initiated with the following aims: 1. To develop a RT-PCR assay for evaluating gene expression concerning renin (REN), angiotensinogen (ATG) and the following ECM components: transforming growth factor-beta 1 (TGF-beta 1), fibronectin (FN), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2); 2. To assess the influence of renal mass reduction (RMR) caused by subtotal (5/6) or partial (2/6) nephrectomy on gene expression for TGF-beta 1, FN, MMP-2 and TIMP-2; 3. To evaluate the correlation between expression of these genes and activity of the circulatory or renal renin-angiotensin systems; 4. To assess the influence of treatment with enalapril (angiotensin-converting enzyme inhibitor) on renal expression of these genes, renal morphology and function in rats, relative to duration of treatment and RMR. The study consisted of two independent experiments performed in adult male Sprague-Dawley rats. Ten days prior to surgery, the animals were matched for body weight and systolic blood pressure (SBP) values and subsequently were distributed into untreated (control) and enalapril treated groups. Treatment with enalapril (EN) (50 mg/l in drinking water) was started 9 days prior to surgery. The first (short-term) experiment was performed in rats with chronic renal failure caused by subtotal nephrectomy. Remnant kidneys were taken for molecular studies at the day of SNx and 3, 7 and 21 days thereafter. Blood samples collected at the time of sacrifice served to determine plasma renin activity and plasma concentration of angiotensinogen and angiotensin II. The second (long-term) experiment was done in subtotally (5/6) and partially (2/6) nephrectomized rats. Remnant kidneys were taken for molecular and morphological studies at the day of surgery and 1 or 16 weeks thereafter. 24-hour proteinuria, hematocrit, serum creatinine and creatinine clearance values were also measured. Quantitation of renal gene expression for REN, ATG, TGF-beta 1, FN, MMP-2 and TIMP-2 was performed using RT-PCR assay and comparing amounts of respective gene mRNA with house-keeping gene mRNA encoding L19 ribosomal protein. The results obtained have led to the following conclusions: 1. The RT-PCR assay developed here ensures a reliable quantitation of gene expression for renin, angiotensinogen, transforming growth factor-beta 1, fibronectin, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2. 2. Renin gene expression in the kidney depends on renal synthesis of angiotensin II. In contrast, regulation of angiotensinogen mRNA expression seems to be independent of ANG II. 3. Long-term treatment with enalapril prevents an early increase in renal TGF-beta 1 and FN gene expression, retards the progression of chronic renal failure caused by critical renal mass reduction, and prolongs survival. 4. Intrarenal activity of the renin-angiotensin system is not a principal factor in the regulation of gene transcription for matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2.
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PMID:[Molecular mechanisms of nephro-protective action of enalapril in experimental chronic renal failure]. 1058 3

The systemic renin-angiotensin system (RAS) is suppressed in normal aging, but the activity of the tissue RAS is not well defined. We examined the systemic and intrarenal RAS status of aging normal rats and responses to suppression and stimulation of the production of endogenous ANG II. Studies were performed in young (3 mo) and early aging (15 mo) male Sprague-Dawley rats. Angiotensin-converting enzyme inhibitors modestly decreased mean arterial pressure (MAP) in young (3 mo) and early aging (15 mo) rats and limited proteinuria in the older rats. There were no significant age-related effects on renal function or on endogenous RAS activity. Intravenous infusion of the precursor ANG I led to comparable increases in MAP in younger and older rats. In contrast, the renal effects (reduction in glomerular filtration and plasma flow rates) were exaggerated in the older animals. Intrarenal arterial ANG I did not affect MAP in any group. In young rats, there were no significant hemodynamic effects in either the ipsilateral (infused) or the contralateral (noninfused) kidney. In the older rats, both kidneys had a significant fall in renal renal plasma flow rate (RPF) with left renal arterial infusion of ANG I. Accordingly, these studies early in the course of aging found only subtle changes in the activity, responsiveness, and metabolism of the RAS. Thus early aging is associated with a modest but important increase in sensitivity to RAS stimulation.
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PMID:Activity and responsiveness of the renin-angiotensin system in the aging rat. 1104 62


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