Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 studied renal function, glomerular cell proliferation and apoptosis for three months after uninephrectomy (UNX) in young, male, spontaneously hypertensive rats (SHR). Apoptosis was assessed by in situ dUTP biotin nick-end labeling method (TUNEL) and by propidium iodide staining. Proliferation rate was determined by immunohistochemistry to proliferating cell nuclear antigen (PCNA). Glomerular bcl-2 expression was assessed by Northern blot analysis. Our results indicate a parallel increase in proliferation and in apoptotic rates in glomerular cells from the first to the second month after UNX. In the third month after UNX, PCNA-labeled cell number continues increasing, whereas TUNEL-labeled cells did not increase. Bcl-2 expression was negative in the first and second months and increased in the third month. Glomerular size and proteinuria increased progressively along the three months of follow-up. Our observations demonstrate a different profile of cell proliferation and apoptosis during the genesis of early glomerular damage in UNX-SHR.
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PMID:Glomerular cell proliferation and apoptosis in uninephrectomized spontaneously hypertensive rats. 983 81

Increased apoptosis of glomerular cells, with progression of glomerulosclerosis, overactivity of the renin-angiotensin system and elevation of glomerular pressure, follows chronic nitric oxide synthase (NOS) inhibition in spontaneously hypertensive rats (SHR). To gain insight into the regulation of glomerular cell apoptosis in severe nephrosclerosis, we investigated apoptosis, the expression of proliferative cell nuclear antigen (PCNA) in glomeruli, and glomerular morphometric changes in 20-week-old SHR, SHR treated with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 80 mg/l in drinking water), and SHR treated with L-NAME and the calcium antagonist, efonidipine (20 mg/kg per day), for 3 weeks. Apoptosis in non-sclerotic glomeruli was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The increase in systolic blood pressure and the severe proteinuria with severe nephrosclerosis induced by chronic NOS inhibition were completely prevented by efonidipine. Furthermore, the glomerular area and capillary tuft area were markedly increased in rats treated with efonidipine compared with both control rats (+30 and +42%, respectively, p<0.01) and rats treated with L-NAME (+35 and +56%, respectively, p<0.01)-treated rats. This calcium antagonist also significantly inhibited the both increases of the glomerular cell apoptosis index (-72%) and the PCNA index (+44%), therefore the alteration between apoptosis and proliferation slightly increased the number of glomerular cells (subcapsular, +22%, p<0.01; juxtamedullary, +2%, not significant). Thus, the calcium antagonist efonidipine seems to play an important role in the regulation of apoptosis and proliferation of glomerular cells and may be effective in preventing nephrosclerosis exacerbated by NOS inhibition.
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PMID:Calcium antagonist inhibits glomerular cell apoptosis and injuries of L-NAME exacerbated nephrosclerosis in SHR. 1113 Dec 82

In proteinuric nephropathies tubular atrophy leads to glomerular-tubule disconnection through an unknown mechanism. Here we studied whether proteinuria promoted glomerular-tubule disconnection in individual nephrons and whether this phenomenon was prevented by an angiotensin-converting enzyme (ACE) inhibitor. Passive Heymann nephritis (PHN) and control rats were studied at 4 and 8 months. Two additional groups of PHN rats received lisinopril (40 mg/L) or a calcium channel blocker (lacidipine, 3 mg/kg) from day 7 after surgery to 8 months. At sacrifice, kidneys were serially sectioned to identify glomerular- tubule abnormalities in individual nephrons and changes in interstitial volume. In PHN rats, the time-dependent increase in proteinuria was paralleled by tubular atrophy leading to glomerular-tubule disconnection and interstitial volume enlargement. Marked apoptosis was invariably found in atrophic tubules in contrast to the absent or very mild terminal dUTP nick-end labeling staining in tubules normally connected to glomeruli in PHN animals. Treatment with an ACE inhibitor prevented hypertension, proteinuria, the formation of atrophic tubuli, glomerular-tubule disconnection and limited the fractional interstitial volume expansion. Although lacidipine limited hypertension, it did not reduce proteinuria or prevent tubular atrophy and disconnection. Multivariate analysis showed that the appearance of atubular glomeruli and the increase in interstitial volume were better predicted by proteinuria than blood pressure. This study suggests that ACE inhibitors effectively prevent glomerular-tubule disconnection possibly by their ability of reducing proteinuria, which in turn favors proximal tubular cell apoptosis. Agents that only reduced hypertension but not proteinuria do not affect tubular behavior.
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PMID:Angiotensin-converting enzyme inhibition prevents glomerular-tubule disconnection and atrophy in passive Heymann nephritis, an effect not observed with a calcium antagonist. 1169 35

Tubular response, including phenotypic changes against a variety of injuries, is an initial event that promotes tubulointerstitial injuries. Using the progressive kidney disease model of rat adriamycin (ADR) nephrosis, the present study focused on the cell cycle activation and phenotypic changes that occur in the tubuli in early tubulointerstitial injury in ADR nephrosis. At 12 weeks, experimental animals developed overt nephrosis with tubulointerstitial injury, which correlated well with the degree of proteinuria and incidence of glomerulosclerosis. Initial pathology of the tubuli showed a slight dilatation of tubuli, which tended to occur in individual nephrons. Immunohistochemistry demonstrated that vimentin-positive tubuli and osteopontin (OPN)-positive tubuli were associated mostly with proliferating cell nuclear antigen expression. Protein levels of OPN in the renal cortex were correlated with the level of proteinuria by western blotting. Vimentin- and OPN-expressing tubuli were tightly associated with a peritubular influx of alpha-smooth muscle actin (SMA)-positive cells or ED-1-positive cells. In addition, we found thrombomodulin+/ TUNEL+ (dUTP-biotin nick-end labeling) peritubular endothelial cells and ED-1+/alpha-SMA+ cells at an early stage among interstitial inflammatory cells. These results suggest that cell cycle activation in tubular cells forms the background for the phenotypic tubular changes that are involved in chronic tubulointerstitial injury in ADR nephrosis.
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PMID:Phenotypic changes and cell cycle activation in early tubulointerstitial injury of rat adriamycin nephrosis. 1197 65

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.
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PMID:Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy. 1469 60

Apoptosis is implicated in the progressive cell loss and fibrosis both at glomerular and tubulointerstitial level. In this study, we examined the potential mechanisms by which persistent proteinuria (protein-overload model) could induce apoptosis. After uninephrectomy (UNX), Wistar rats received daily injections of 0.5 g of bovine serum albumin (BSA)/100 g body weight or saline. Both at day 8 and day 28, rats receiving BSA had proteinuria and renal lesions characterized by tubular atrophy and/or dilation and mononuclear cell infiltration. In relation to control-UNX rats, renal cortex of nephritic rats showed an increment in AT2 mRNA (reverse transcriptase-polymerase chain reaction) and protein (Western blot) expression. In both groups, AT2 receptor immunostaining was mainly localized in proximal tubular cells. Rats with persistent proteinuria showed a significantly increased number of terminal dUTP nick-end labeling positive apoptotic cells compared with UNX-controls, both in glomeruli and tubulointerstitium. Double staining for apoptosis and AT2 receptor showed that most terminal dUTP nick-end labeling positive cells were found in tubules expressing AT2 receptor. Using an antibody that recognizes the active form caspase-3, we observed an increment in caspase-3 activation in rats receiving BSA with respect to those receiving saline. Rats with persistent proteinuria showed a diminution in the phosphorylation of Bcl-2 with respect to UNX-controls both at day 8 and day 28. By contrast, no changes were observed either in the Bax or in the Bcl-2 protein levels. The administration of BSA to UNX rats induced a diminution in the phosphorylation of ERK with respect to UNX-control at all times studied. The changes observed in ERK activities took place without alterations of ERK1/2 protein levels. In summary, our data suggest that persistent proteinuria causes apoptosis in tubular cells through the activation of AT2 receptor, which can, in turn, inhibit MAP kinase (ERK1/2) activation and Bcl-2 phosphorylation.
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PMID:Persistent proteinuria up-regulates angiotensin II type 2 receptor and induces apoptosis in proximal tubular cells. 1511 28

Accumulating evidence demonstrates that oxidative stress is one of the underlying mechanisms to induce apoptosis in different biological systems. The aim of this study was to examine the simultaneous presence and correlation between oxidative stress events, apoptosis, apoptosis-associated proteins and monocyte/macrophage infiltration during the course of acute puromycin aminonucleoside nephrosis (PAN). To induce nephrosis, Sprague-Dawley rats were injected intraperitoneally with puromycin aminonucleoside and killed at weeks 1 and 2 of nephrosis. Controls represent animals injected with 0.9% saline solution. Kidney sections were homogenized to measure nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase activities by appropriate enzymatic and biochemical methods. Renal frozen sections were studied for superoxide anion (O(2) (-)) by a histochemical method, for apoptosis by TUNEL (terminal-deoxynucleotidyl-transferase-mediated dUTP- digoxigenin nick end labelling) and for apoptosis-associated protein expression and monocyte/macrophage infiltration by monoclonal antibodies. Increased renal apoptosis, p53, Bax, Bcl-2 accompanied by increased O(2) (-) and NO generation, lipid peroxidation (MDA) and monocyte/macrophage infiltration were found in nephrotic animals. Renal oxidative stress (O(2) (-), NO and MDA) was correlated with apoptosis, p53 expression, monocyte/macrophage cells and proteinuria. Anti-oxidant molecules (SOD and GSH) remained unchanged apart from a decreased activity of catalase which correlated with glomerular apoptosis. In conclusion, the close correlation between the presence of apoptosis and oxidative events confirms the role of oxidative stress in the apoptosis observed during PAN.
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PMID:Increased oxidative stress and apoptosis in acute puromycin aminonucleoside nephrosis. 1511 91

Apoptotic glomerular cells have been detected in the severely damaged glomeruli that are a consequence of human IgA nephropathy. Transforming growth factor-(TGF) beta1 is known to induce apoptosis in cultured mesangial cells. To clarify whether TGF-beta1 contributes to the progression of IgA nephropathy by activating apoptosis in glomerular cells, we examined the expression of TGF-beta1 gene and apoptotic changes in kidney biopsy samples, and assessed those relations to the severity of nephropathy. 32 patients with IgA nephropathy, showing proteinuria (> 1 g/day) and serum creatinine less than 1.5 mg/dl were classified according to glomerular sclerosis index (GSI) into 3 groups (Group I: GSI < 0.3,Group 11: 0.3 < or = GSI < 1.0, Group: III GSI > or = 1.0). Computer-aided morphometry of glomeruli and arteries, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling of fragmented DNA (TUNEL) staining were performed. Expression of TGF-beta1 and caspase-3 mRNAs in renal biopsy samples was analyzed by real-time PCR (Taq Man method). Increased glomerular area, interstitial fibrosis, lymphocytic infiltration, and tubulointerstitial changes were observed to accompany increased severity of GSI. TUNEL index was higher in Group III. The levels of TGF-beta1 and caspase-3 mRNAs were significantly increased in Group III (183 and 190%, respectively). Furthermore, caspase-3 mRNA levels were tightly associated with TGF-beta1 mRNA expression (r = 0.677, p < 0.0001). The present study suggests that the activation of TGF-beta1 plays a role in the progression of IgA nephropathy even in the moderate degree of glomerular injury, in part via activation of apoptosis of glomerular cells.
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PMID:Roles of TGF-beta1 and apoptosis in the progression of glomerulosclerosis in human IgA nephropathy. 1679 32

A decline in podocyte number correlates with progression to glomerulosclerosis. A mechanism underlying reduced podocyte number is the podocyte's relative inability to proliferate in response to injury. Injury by the podocyte toxin puromycin aminonucleoside (PA) is mediated via reactive oxygen species (ROS). The precise role of ROS in the pathogenesis of PA-induced glomerulosclerosis remains to be determined. We sought to examine whether PA-induced ROS caused podocyte DNA damage, possibly accounting for the podocyte's inability to proliferate in response to PA. In vitro, podocytes were exposed to PA, with or without the radical scavenger 1,3-dimethyl-2-thiourea (DMTU). In vivo, male Sprague-Dawley rats were divided into experimental groups (n = 6/group/time point): PA, PA with DMTU, and control, killed at days 1.5, 3, or 7. DNA damage was measured by DNA precipitation, apurinic/apyrimidinic site, Comet, and 8-hydroxydeoxyguanosine assays. Cell cycle checkpoint protein upregulation (by immunostaining and Western blotting), histopathology, and biochemical parameters were examined. DNA damage was increased in cultured podocytes that received PA, but not PA with DMTU. PA exposure activated specific cell cycle checkpoint proteins, with attenuation by DMTU. DNA repair enzymes were activated, providing evidence for attempted DNA repair. The PA-treated animals developed worse proteinuria and histopathologic disease and exhibited more DNA damage than the DMTU pretreated group. No significant apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. A mechanism underlying the lack of podocyte proliferation following PA-induced injury in vitro and in vivo may be ROS-mediated DNA damage, with upregulation of specific cell cycle checkpoints leading to cell cycle arrest.
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PMID:Puromycin aminonucleoside induces oxidant-dependent DNA damage in podocytes in vitro and in vivo. 1703 36

Previous studies have shown that mineralocorticoid receptor (MCR) blocker reduces proteinuria in diabetic nephropathy (DN), but the role of aldosterone in podocyte injury has never been explored in DN. This study was undertaken to elucidate whether a local aldosterone system existed in podocytes and to examine its role in podocyte apoptosis under diabetic conditions. In vitro, immortalized podocytes were exposed to 5.6 mM glucose (NG), NG + 24.4 mM mannitol, and 30 mM glucose (HG) with or without 10(-7) M spironolactone (SPR). In vivo, 32 Sprague-Dawley rats were injected with diluent (C, n = 16) or streptozotocin intraperitoneally [diabetes mellitus (DM), n = 16], and 8 rats from each group were treated with SPR for 3 mo. Aldosterone synthase (CYP11B2) and MCR mRNA and protein expression were determined by real-time PCR and Western blot, respectively, and aldosterone levels by radioimmunoassay. Western blot for apoptosis-related molecules, Hoechst 33342 staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to determine apoptosis. CYP11B2 and MCR expression were significantly higher in HG-stimulated podocytes and DM glomeruli compared with NG cells and C glomeruli, respectively, along with increased aldosterone levels. Western blot analysis revealed that cleaved caspase-3 and Bax expression was significantly increased, whereas Bcl-2 expression was significantly decreased in HG-stimulated podocytes and in DM glomeruli. Apoptosis determined by Hoechst 33342 staining and TUNEL assay were also significantly increased in podocytes under diabetic conditions. These changes in the expression of apoptosis-related proteins and the increase in apoptotic cells were inhibited by SPR treatment. These findings suggest that a local aldosterone system is activated and is involved in podocyte apoptosis under diabetic conditions.
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PMID:Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions. 1971 Feb 42


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