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 have studied the sequential morphological changes that took place in the kidneys of 8 rats with nephrotoxic serum nephritis (NTN). Rats underwent kidney biopsies at different time intervals (days 7, 15, 30, 90 and 120). The tissues were processed for light microscopy as well as immunohistochemistry for inflammatory cellular infiltrate as well as for the components of the extracellular matrix (ECM) and myofibroblasts (cells expressing alpha-smooth muscle actin, alpha-SMA). Nephrotic rats developed severe proteinuria, impaired renal function as well as progressive renal scarring. However, the natural history of NTN was heterogeneous with some rats recovering (n = 5) and other progressing to end-stage renal failure (n = 3). The heterogeneous nature of the glomerulonephritis has established that those with a good outcome had a stabilisation, with some resolution, of the deposited ECM and of the scarring process. By contrast, rats with a poor outcome had a progressive increase in glomerular as well as interstitial ECM. Cells expressing alpha-SMA (myofibroblasts) were detected in the glomeruli as well as in the interstitium of nephritic rats. Changes in the expression of cells expressing alpha-SMA paralleled those of the components of the ECM in particular fibronectin. alpha-SMA immunostain was the best predictor of progression. Early glomerular alpha-SMA immunostain (days 7 and 30) was a strong predictor of the subsequent development of glomerulosclerosis and renal dysfunction. The predictive value of interstitial alpha-SMA immunostain on days 7 for subsequent tubulo-interstitial scarring and renal insufficiency was also strong and exceeded that of other histological or immunohistochemical parameters of scarring. This study establishes the natural history of experimental renal scarring and identifies a renal cell type, the myofibroblast, as a useful marker of progression. It also suggests a role for myofibroblasts in the progression of glomerulosclerosis and tubulo-interstitial fibrosis.
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PMID:Myofibroblasts and the progression of experimental glomerulonephritis. 758 53

Myofibroblasts play an important role in wound healing in a variety of tissue injuries. They have also been implicated in tissue fibrosis including renal scarring. This study was aimed at defining their role in one of the commonest forms of nephrotic syndrome in adults, namely membranous nephropathy. We have studied 21 patients with biopsy proven idiopathic membranous nephropathy who were treated with glucocorticoids, attempting to define the role of myofibroblasts (alpha-smooth muscle actin-positive as well as vimentin-positive cells) in the progression of this form of nephropathy. There were 13 non-progressors (NP) and 8 progressors (P). The clinical, histological, and immunohistochemical characteristics of both groups were compared. Immunohistochemical staining for myofibroblasts cytoplasmic markers a-smooth muscle actin (alpha-SMA) and vimentin relied on an avidin-biotin-peroxidase method. The level of blood pressure, degree of proteinuria, severity of interstitial infiltrate and interstitial fibrosis did not differentiate P from NP. However, vascular sclerosis was more severe in P compared to NP (p < 0.016) and its severity predicted the subsequent functional outcome (slope of the 1/serum creatinine against time; r2 = 0.618, p < 0.01). Mesangial alpha-SMA was significantly higher in P (31 +/- 18.6%) than in NP (14.5 +/- 9.8%), p < 0.015. Interstitial alpha-SMA immunostain was also higher in P but did not reach statistical significance. However, the number of interstitial myofibroblasts (alpha-SMA positive cells) closely predicted the subsequent rate of the progression of chronic renal failure (r2 = 0.919, p < 0.0001). Mesangial vimentin expression was not different between both groups. By contrast, interstitial vimentin immunostain was higher in P (19.1 +/- 8.8%) compared to NP (7.9+/-5.6 %), p < 0.002. These data suggest that the expression of mesangial and interstitial cytoskeletal proteins (alpha-SMA and vimentin) may have useful prognostic implications as they appear to differentiate between patients with membranous nephropathy who respond to immunosuppression and those who continue to progress.
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PMID:Expression of cytoskeletal proteins differentiates between progressors and non-progressors in treated idiopathic membranous nephropathy. 963 37

The aim of the current study was to characterize the effects of prolonged hyperglycemia on renal structure and function using a model of non-insulin-dependent diabetes mellitus: the Goto Kakizaki (GK) rat, which does not have confounding variables, such as hyperlipidemia, obesity, or elevated blood pressure. The data show that hyperglycemia in this model was not associated with the development of significant proteinuria, but it was associated with the development of definitive age-dependent renal structural changes. These changes consisted of thickening of glomerular basement membrane at 35 weeks and tubular basement membrane. This thickening was accompanied by marked glomerular hypertrophy resulting from a parallel increase in total capillary luminal volume and mesangial volume, but fractional capillary and mesangial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidence of mesangial cell activation, as assessed by their de novo expression of alpha-SMA. Interstitial monocyte/macrophage influx increased significantly in GK rats at 12 weeks compared with Wistar controls. Glomerular macrophage infiltration was elevated significantly in 35-week GK rats. The structural changes described in the GK rat are similar to those described in prolonged non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechanisms involved in the pathogenesis of the consequences of prolonged hyperglycemia.
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PMID:Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus. 1115 83

The aim of this study was to evaluate whether the infiltrating T-lymphocyte can be a predictor in the disease progression of IgA nephropathy (IgAN). Twenty children with IgAN, followed for more than 5 years, were divided into progressive (n=5) and non-progressive groups (n=15). We assessed glomerular and interstitial infiltration of T-lymphocytes (CD4+ and CD8+ cells) and expression of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta (TGF-beta) using an indirect immunofluorescence method on the renal biopsies. We analyzed their relationship to the degree of proteinuria, histological changes, and prognosis. The number of CD8+ cells in glomeruli and in interstitium was higher in the progressive group than in the non-progressive group. The glomerular alpha-SMA staining was more intensive in the progressive group than in the non-progressive group. Urinary protein and the degree of histological changes were also higher in the progressive group than in the non-progressive group. Among these markers, the number of glomerular CD8+ cells was the most apparent difference between the two groups. In conclusion, these results indicate that the number of glomerular CD8+ cells is the most sensitive predictor of disease progression in childhood IgAN.
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PMID:Glomerular CD8+ cells predict progression of childhood IgA nephropathy. 1146 5

Thy-1 nephritis was induced in stroke-prone spontaneously hypertensive rats (SHR-SP) with unilateral nephrectomy (UNX) and normotensive same genetic strain Wistar-Kyoto (WKY) rats with UNX to evaluate whether the tubulointerstitial injury in Thy-1 nephritis is accelerated by long-term systemic and intraglomerular hypertension. SHR-SP that underwent UNX at twelve weeks of age were randomly assigned to receive monoclonal anti-thy 1.1 antibody (group SP), and normal saline (group SC). Age-matched normotensive WKY rats served as controls and were given the same dose of monoclonal anti-thy 1.1 antibody after UNX (group WK). In all groups, the blood pressure and renal function were assessed, and morphologic changes of tubulointerstitium were examined by using immunohistochemistry and light microscopy twelve weeks after Thy-1 nephritis induction (in groups SP and WK) and UNX alone (in group SC). In all groups, histological findings, the degree of monocyte/macrophage infiltration, interstitial expression of alpha-smooth muscle actin (alpha-SMA), which is a marker for myofibroblasts, and the degree of tubular cell proliferation were examined. In addition, assessments of blood pressure, serum creatinine and BUN levels, and the degree of proteinuria were made. In parallel to glomerular structural damage, interstitial fibrosis with predominant monocyte/macrophage influx, increased interstitial expression of alpha-SMA and tubular cell proliferation were observed in group SP. A significant increase in serum creatinine and proteinuria were also present in this group. In contrast, the changes observed in group SC were not so evident or extensive as in group SP. The level of proteinuria was lower than that in group SP. No evident tubulointerstitial changes were found in group WK. The results showed that tubulointerstitial injury was prominently progressed in the hypertensive model with Thy-1 nephritis. This suggests that sustained systemic and glomerular hypertension is not only ultimately responsible for the progression of immunologically mediated glomerular injury, but is also responsible for subsequent tubulointerstitial changes. Migration and proliferation of myofibroblasts and intense influx of monocytes/macrophages may contribute to the development of tubulointerstitial fibrosis.
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PMID:Tubulointerstitial injury of Thy-1 nephritis in uninephrectomized stroke-prone spontaneously hypertensive rats. 1150 77

Glomerular endothelial nitric oxide synthase expression is decreased in humans during acute rejection and chronic renal transplant failure (CRTF). This may contribute to vascular damage through changes in the renal hemodynamics and enhanced endothelial adhesion of leukocytes and platelets. Dietary supplementation of L-arginine may increase endothelial NO production, thereby protecting the vascular wall and improving renal hemodynamics. We tested the hypothesis that long-term L-arginine supplementation attenuates the development of CRTF in an experimental model for renal transplantation. In the Fisher 344 to Lewis rat model for renal transplantation, renal function and histology of untreated rats was compared with rats receiving L-arginine in the drinking water (10g/L), starting 2 days before transplantation. Every 4 weeks systolic blood pressure was measured and serum and urine were collected for measurement of nitrite and nitrate (NO(x)), creatinine, and proteinuria. At 34 weeks the histological renal damage was assessed by scoring focal glomerulosclerosis and measurement of alpha-smooth muscle actin (alpha-SMA) expression. Urinary NO(x) was significantly increased in treated animals. Proteinuria was significantly lower in L-arginine-treated animals from week 24 onward (p<0.05). Plasma creatinine and creatinine clearance did not differ between the groups. The focal and segmental glomerulosclerosis (FGS) score (max 400) at week 34 was also significantly lower in treated rats arbitrary U (20+/-21 vs 61+/-67 arbitrary U; p<0.05). The expression of alpha-SMA was lower in L-arginine-treated rats than in untreated rats (1.93+/-0.8% area surface vs 3.64+/-2.5% area surface). In conclusion, in this experimental model for CRTF, L-arginine administration significantly reduced FGS and proteinuria, without affecting renal function. Our data suggest that dietary L-arginine supplementation attenuates progression of CRTF and may therefore be an additional therapeutic option in human renal allograft recipients.
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PMID:Long-term dietary L-arginine supplementation attenuates proteinuria and focal glomerulosclerosis in experimental chronic renal transplant failure. 1258 42

It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for alpha-smooth muscle actin (alpha SMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-beta 1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.
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PMID:Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. 1276 Dec 50

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


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