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)

ACE inhibition (ACEi) reduces proteinuria and provides reno-protection, but not all subjects benefit from ACEi. Individual differences in the reduction in proteinuria at the onset of treatment and in residual proteinuria during therapy predict differences in renal outcome. The present study investigated whether individual differences in the anti-proteinuric efficacy of ACEi are explained by differences in the severity of pretreatment renal structural damage and whether differences in the level of residual proteinuria during therapy are explained by the severity of renal structural damage at that time, in adriamycin nephrosis in the rat. Pretreatment renal structural damage was assessed in biopsies 6 weeks after exposure to adriamycin (2 mg/kg iv). Then ACEi (75 mg/l lisinopril, n = 23) or vehicle (n = 10) was administered; renal biopsies were repeated after stabilization of the anti-proteinuric response (week 8). Early renal damage (interstitial alpha-smooth muscle actin expression and macrophage accumulation) and established lesions [focal glomerulosclerosis (FGS) and interstitial fibrosis] were scored. During ACEi, proteinuria fell from 834 (487-851) mg/24 h pretreatment to 153 (66-265) mg/24 h at week 8 (p < 0.05); FGS stabilized from 27 (4-70) arbitrar units (AU) pretreatment to 26 (4-84) at week 12, whereas the vehicle did not affect proteinuria, resulting in progressive FGS: 18 (10-26) AU pretreatment versus 88 (46-130) at week 12 (p < 0.05). All parameters of pretreatment damage significantly predicted the anti-proteinuric response. Residual proteinuria during ACEi correlated significantly with renal structural damage parameters at that time. Pretreatment renal damage also predicted renal outcome during extended treatment. Thus, in this experimental setting, in rats with the same renal disorder and the same duration of disease, individual differences in pretreatment renal damage, albeit relatively modest, explain individual differences in renal responsiveness to ACEi. This implies that the limits of the efficacy of ACEi are set by prevalent renal damage. Further studies into the mechanisms of individual resistance to the anti-proteinuric action of ACEi are needed to develop additive intervention strategies.
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PMID:Inter-individual differences in anti-proteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pretreatment renal damage. 1295 29

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.
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PMID:L-arginine as a therapeutic tool in kidney disease. 1525 78

Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal and segmental sclerosis. The role of oxidative and nitrosative stress in the nephropathy in ZDF was studied. Renal histology, function, and immunohistologic and biochemical parameters of oxidative and nitrosative stress were evaluated at 8 and 22 wk of age in ZDF and Zucker lean (ZL) rats and after chronic treatment with ebselen, an antioxidant and peroxinitrite scavenger. At 8 wk, ZDF rats showed hyperglycemia, no proteinuria or nephropathy, but higher levels of dihydrobiopterin and 3-nitrotyrosine (3-NT)-modified proteins compared with age-matched ZL rats. At 22 wk, ZDF rats developed focal and segmental sclerosis, proteinuria, decreased creatinine clearance, and renal tissue levels of glutathione and tetrahydrobiopterin with further elevation in dihydrobiopterin and 3-NT-modified proteins, in contrast to age-matched ZL rats. Renal immunohistologic expression of lipid peroxidation products and 3-NT-modified proteins also increased in 22-wk-old ZDF but not in ZL rats. Chronic ebselen treatment of ZDF rats restored renal tissue levels of glutathione and tetrahydrobiopterin; prevented significant accumulation of dihydrobiopterin, lipid peroxidation products, and 3-NT-modified proteins; and ameliorated focal and segmental sclerosis, proteinuria, and fall in creatinine clearance without affecting mean BP, body weight, and blood glucose, compared with the untreated ZDF rats. Chronic ebselen therapy also ameliorated vasculopathy with lipid deposits and tubulointerstitial scarring, inflammation, and upregulated alpha-smooth muscle actin expression. These findings suggest that ZDF rats develop a progressive nephropathy with glomerular, vascular, and tubulointerstitial pathology. Oxidative and nitrosative stress predates the nephropathy, which is improved by peroxinitrite scavenger ebselen, and thus considered its cause and not consequence.
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PMID:Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: prevention by chronic therapy with a peroxynitrite scavenger ebselen. 1533 88

Epithelial-to-mesenchymal transition (EMT) and oxidative stress contribute to kidney tissue fibrosis in various forms of native kidney disease. However, their role in chronic allograft nephropathy (CAN) remains somewhat uncertain. To address this question, kidney transplants were performed in 3-month-old rats, using the Fisher 344 --> Lewis model of CAN. Six-month posttransplant, kidney allografts displayed significant tubular atrophy, interstitial fibrosis and vascular wall thickening. Allograft recipients had significantly higher levels of serum creatinine (4.7 +/- 1.3 versus 0.59 +/- 0.08 mg/dL, p = 0.03) and proteinuria (380 +/- 102 versus 30.2 +/- 8 mg/dL, p = 0.04) compared to syngeneic grafts. Semiquantitative PCR, immunoblot and immunohistochemical analyses demonstrated increased alpha-smooth muscle actin (alpha-SMA) mRNA and protein levels coupled with reduced E-cadherin mRNA and protein immunoreactivity, confirming the presence of CAN-associated EMT. Allograft alpha-SMA levels were increased as early as 1-2 weeks posttransplant. Immunohistochemical studies for collagen type I and III, superoxide anion (O(2) (-)), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) confirmed that tubular O(2) (-), eNOS and iNOS, and interstitial collagen I, III and O(2) (-) levels were significantly increased in CAN-associated EMT. In conclusion, these observations suggest that CAN-associated EMT may be a link between oxidative stress and allograft fibrosis.
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PMID:Epithelial-to-mesenchymal transition and oxidative stress in chronic allograft nephropathy. 1570 4

Tonsillectomy often improves clinical features in immunoglobulin A nephropathy (IgAN), however, the mechanisms mediating clinical modifications are unclear. In the present study, we examined the immunohistological alterations in biopsy specimens obtained from IgAN patients before and after tonsillectomy. We investigated eight IgAN patients who underwent repeated renal biopsy in the present study. Immunohistochemistry for alpha-smooth muscle actin (alpha-SMA), CD68 and proliferating cell nuclear antigen (PCNA) were performed and histological findings were compared before and after tonsillectomy. None of the patients were treated with steroids or immunosuppressive drugs before second renal biopsy. The expression of alpha-SMA and the number of CD68 positive cells were significantly decreased in IgAN patients with improvement of proteinuria and hematuria after tonsillectomy. The degree of mesangial cell proliferation, expansion of mesangial area and the number of PCNA positive cells were not changed after tonsillectomy. These results suggest that the reduced number of activated mesangial cells and macrophages may be involved in the improvement of hematuria after tonsillectomy. They also suggest that tonsillectomy may improve proteinuria and hematuria in some patients with IgAN through reduction of mesangial cell activation and macrophage infiltration.
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PMID:Clinical and immunohistochemical study of immunoglobulin A nephropathy (IgAN) before and after tonsillectomy. 1576 92

Recent evidence suggests a role for mast cells in the pathogenesis of renal scarring in various glomerulopathies, therefore the present study was undertaken to evaluate whether mast cells have a role in tubulointerstitial fibrosis in rebiopsied patients with idiopathic mesangial proliferative glomerulonephritis (MPG) and to examine a possible relationship between mast cells and interstitial alpha-smooth muscle actin (alpha-SMA) expression as well as interstitial infiltrates. Seventeen patients with idiopathic mesangial proliferative glomerulonephritis, in whom renal biopsies were repeated and for whom light and electron microscopy as well as immunofluorescence microscopy and full clinical data were available were examined quantitatively. Morphometric investigations were performed by means of a computer image analysis system. The study revealed that at the rebiopsy proteinuria was significantly lower as compared with the first biopsy. On the other hand, the mean values of the interstitial tryptase positive cells, expression of alpha-SMA, interstitial volume and CD68+ cells were at rebiopsy significantly increased. The mean values of CD45RB+, CD43+ and CD20+ cells did not differ significantly in these groups. In both initial biopsy and rebiopsy groups there were significant positive correlations between interstitial tryptase positive cells and interstitial expression of alpha-SMA, interstitial volume, and CD68+ cells. The present quantitative study may suggest that despite of the clinical improvement at rebiopsy, MPG is a progressive glomerular disease, and point to a role of mast cells in this process.
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PMID:Immunohistochemical analysis of the interstitial mast cells in rebiopsied patients with idiopathic mesangial proliferative glomerulonephritis. 1609 67

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.
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PMID:Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis. 1621 43

We reviewed the clinical, histological and serological parameters of microscopic polyangiitis (MPA) associated with antineutrophil cytoplasmic antibodies (ANCA) specific to myeloperoxidase (MPO). Six girls and one boy aged 12.0+/-2.6 years (7-15 years) met the following inclusion criteria: (1) clinical manifestations of systemic small vessel involvement; (2) histological demonstration of pauci-immune necrotizing glomerulonephritis; and (3) serological findings of increased concentration of MPO-ANCA by ELISA test. The main clinical manifestations were: influenza-like symptoms (100%), hematuria/proteinuria (100%), purpura (100%), pulmonary-renal syndrome (57%), acute renal failure (ARF) (29%), ischemic cerebral insults (29%), and necrotizing vasculitis of the skin (29%). All patients underwent renal biopsy examined by immunohistochemistry with expression of alpha-smooth muscle actin (alpha SMA) in glomerular and interstitial spaces. Patients were followed from 6 months to 5.5 years (35.4+/- 23.2 months). None of the patients died. Two of seven children who had ARF progressed to end stage renal disease; one developed chronic renal failure, and four normalized renal function. ARF and central nervous system involvement at presentation were parameters of poor renal outcome. A high score of fibro-cellular glomerular crescents was associated with worse prognosis. Early treatment enables a favorable prognosis of MPO-ANCA-associated MPA in children.
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PMID:Childhood microscopic polyangiitis associated with MPO-ANCA. 1625

Angiotensin II can induce oxidant stress by stimulating vascular superoxide production. Hypertension promotes mitochondrial function decline in brain, liver and heart. The aim of this study was to investigate whether a) hypertension is associated to kidney mitochondrial dysfunction, and b) angiotensin II blockade can reverse potential mitochondrial changes in hypertension. Four-month-old male spontaneously hypertensive rats (SHR) received drinking water containing candesartan (7.5 mg/kg/day, SHR+Cand), or no additions (SHR) for 4-months. Eight-month-old Wistar-Kyoto rats (WKY), that received water with no additions, were used as control. Systolic blood pressure, proteinuria, cortical glomerular area, and glomerular and tubulointerstitial alpha-smooth muscle actin labeling, were significantly higher, and creatinine clearance was significantly lower, in SHR relative to WKY and SHR+Cand. In SHR, kidney mitochondria membrane potential, and nitric oxide synthase and cytochrome oxidase activities were significantly lower than in WKY and SHR+Cand. In SHR, mitochondrial hydrogen peroxide production was significantly higher than in WKY and SHR+Cand. The results suggest that, in hypertension, increased mitochondrial oxidant production may mediate kidney mitochondria dysfunction. Candesartan preserved mitochondrial function, probably favoring the maintenance of adequate cellular and tissue function in the kidney. The known renal protective effects of candesartan in hypertension may be related to the improvement of mitochondrial function. This may be an additional or alternative explanation for some of the beneficial effects of AT1 receptor antagonists.
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PMID:Angiotensin II blockade improves mitochondrial function in spontaneously hypertensive rats. 1630 82

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.
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PMID:ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease. 1660 78


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