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ABSTRACT: BACKGROUND: There is no reliable clinical test to predict the reversibility of acute-on-chronic renal failure. We study whether urinary biomarkers could be used as a noninvasive prognostic marker in patients with acute-on-chronic renal failure. METHODS: We studied 39 adult patients with pre-existing chronic renal impairment presenting to us with acute-on-chronic renal failure. Urinary neutrophil gelatinase-associated lipocalin (NGAL) level was measured. The mRNA of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), alpha-1-microglobulin (α1M), sodium/hydrogen exchanger-3 (NHE3), beta-2 microglobulin (β2M), and N-acetyl-β-D-glucosaminidase (NAG) in urinary sediment were quantified.RESULTS: Urinary NGAL level significantly correlated with the serum creatinine at presentation (r=0.762, p< 0.0001) but not baseline serum creatinine. Urinary sediment β2M expression significantly correlated with baseline glomerular filtration rate (GFR) (r= -0.400, p=0.012). Urinary α1M and NHE3 expressions were significantly higher in ischemic acute tubular necrosis than other causes of acute kidney injury (p< 0.0001 and p=0.006, respectively). Urinary α1M expression significantly correlated with the degree of improvement in renal function (r=0.387, p=0.026), as well as the estimated GFR 6 months later (r=0.386, p=0.027).CONCLUSION: In patients with acute-on-chronic renal failure, urinary NGAL level correlates with the severity of renal failure, while urinary α1M expression correlates with the degree of renal function recovery. Quantification of urinary α1M mRNA may be developed as an non-invasive tool for risk stratification of this group of patients.
Disease markers 01/2013; · 1.64 Impact Factor
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ABSTRACT: The role of microRNAs (miRNAs) in peritoneal transport is uncertain.
We studied 82 new peritoneal dialysis (PD) patients, 22 prevalent patients without ultrafiltration problem, and 6 patients with documented ultrafiltration problem. Peritoneal transport was determined by standard peritoneal equilibration test (PET). RNA was extracted from the PD effluent after PET, and intra-peritoneal expression of miRNA targets were quantified.
There were significant difference in the PDE expressions of miR-15a and miR-21. There were modest inverse correlations between ultrafiltration volume and PDE expression of miR-17 (r= -0.198, p =0.041) and miR-377 (r=-0.201, p=0.041). There was an inverse correlations between dialysate-to-plasma creatinine concentration at 4 hours and PDE expression of miR-192 (r=-0.199, p=0.040); while mass transfer area coefficient of creatinine correlated with PDE expression of miR-192 (r=-0.191, p=0.049) and miR-377 (r=0.201, p=0.041). Amongst 7 randomly selected patients who had repeat PET after one year, there was a significant correlation between baseline PDE expression of miR-377 and change in ultrafiltration volume (r=-0.852, p=0.015).
The miRNA expression in PDE, including miR-15a, miR-17, miR-21, miR-30, miR-192, and miR-377, correlated with peritoneal transport characteristics. Our result suggests that miRNA may play a role in the regulation of peritoneal membrane function.
Disease markers 01/2012; 33(1):35-42. · 1.64 Impact Factor
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ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by disease flares and remission. We hypothesize that in clinically quiescent SLE patients, the mRNA level of target genes in the urinary sediment is an early indicator of disease flare.
From a cohort of 134 adult SLE patients prospectively followed for 56 weeks, we identified 19 patients with a single disease flare. The mRNA level of eight pre-defined target genes in their urinary sediment before disease flare was compared to 19 matched controls with no disease flare during the same period.
Urinary mRNA level remained static in the control group during the study period. Before disease flare, there was a significant increase in the mRNA level of monocyte chemotactic protein (MCP)-1 and forkhead box P3 (FOXP3), and decrease in interleukin (IL)-17 and GATA-3, in the urinary sediment. The mRNA level of FOXP3 in urinary sediment increases 8 weeks prior to a flare, which precedes the corresponding change in serum complement and anti-DNA antibody titer, while that of MCP-1, IL-17, and GATA3 began to change 4 weeks prior to a flare. The same pattern of change in urinary mRNA level was observed in patients with mild-to-moderate or severe flare, and those with renal or non-renal flare. The SLE Disease Activity Index (SLEDAI) score at the time of flare significantly correlated with the change in urinary level of IL-17 (r=-0.462, p=0.046) and GATA-3 (r=-0.455, p=0.05), but not MCP-1 or FOXP3, prior to the flare.
Monitoring of MCP-1, IL-17, GATA-3 and FOXP3 mRNA level in urinary sediment may provide an early clue for detecting disease flare in SLE patients.
Clinica chimica acta; international journal of clinical chemistry 11/2011; 413(3-4):448-55. · 2.54 Impact Factor
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ABSTRACT: Endotoxin (ET) is recognized to cause adverse effects on cardiovascular (CV) structure. Circulatory translocation of gut bacterial ET is described in heart failure. Chronic kidney disease (CKD) is common in older people and aggressive BP control is the cornerstone of management. We therefore studied ET after improvement of the overall CV milieu with introduction of optimized antihypertensive therapy (AHT).
We recruited 40 hypertensive nondiabetic patients (≥70 years) with CKD stages 3 and 4 and hypertensive non-CKD matched controls. Assessment was performed after complete AHT washout and repeated after AHT reintroduction to target BP 130/80 mmHg. Pulse wave velocity (PWV) and analysis were assessed by applanation tonometry, central hemodynamics by continuous digital pulse wave analysis, vascular calcification (VC) by superficial femoral artery CT, and serum ET by Limulus Amebocyte assay.
Mean age was 76 ± 5 years, estimated GFR (eGFR) (CKD group) was 40 ± 14 ml/min per 1.73 m(2), and achieved BP was 128/69 mmHg. Washout ET was 0.042 ± 0.011 EU/ml and was independent of renal function, gender, age, BP, VC, arterial stiffness, and high-sensitivity C-reactive protein. ET significantly decreased with AHT (to 0.020 ± 0.028 EU/ml; P < 0.001) and was associated with eGFR (R = -0.38; P = 0.02), arterial wave reflection (Augmentation Index R = -0.42; P = 0.01), and degree of tonic vasodilatation (total peripheral resistance R = -0.37; P = 0.03), but not VC, PWV, gender, age, BP, or high-sensitivity C-reactive protein.
Elderly patients with hypertension have elevated serum ET. Improvement of their CV status with optimized AHT is associated with a significant reduction in endotoxemia. Further investigation of the potential pathophysiological mechanisms linking CV disease and CKD with this previously unappreciated effect of AHT appears warranted.
Clinical Journal of the American Society of Nephrology 08/2011; 6(10):2389-94. · 5.23 Impact Factor
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ABSTRACT: BACKGROUND: Connective tissue growth factor (CTGF) and vascular endothelial cell growth factor (VEGF) have been implicated as important effectors during cardiac remodeling. This study tested the hypothesis that norepinephrine (NE) induces CTGF and VEGF gene and protein expression in cardiac fibroblasts (CF) and the CTGF/VEGF complex will have an effect on angiogenesis. METHODS AND RESULTS: Rats CF were cultured in NE (0.01 to 100μM) for 24h. CTGF and VEGF gene expression were measured by quantitative-PCR. CTGF protein and CTGF/VEGF complex were detected by Western blot. The effect of CTGF/VEGF complex on angiogenesis was detected by endothelial cell tube formation assay. VEGF antigen level, reactive oxygen species (ROS) production were measured by ELISA and DCFH-DiOxyQ assay respectively. NE at 0.01μM up-regulated CTGF mRNA and secretory protein expression significantly whereas at 100μM both gene and protein were down-regulated significantly when compared with controls. At 0.01 to 0.1μM of NE, there was no change in VEGF gene and protein level. NE at 100μM increased VEGF gene and antigen level and ROS production significantly when compared with controls. CTGF/VEGF complex was found to inhibit the angiogenesis of endothelial cells. CONCLUSIONS: NE regulates CTGF and VEGF expression in a dose-dependent manner and via VEGF can induce angiogenesis. This work suggests NE may have an important role in ventricular remodeling.
International journal of cardiology 06/2011; · 7.08 Impact Factor
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ABSTRACT: The interplay between intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) might play important roles in the pathogenesis of hypertensive nephrosclerosis (HTN), but human data are limited.
Renal biopsy specimens of 41 patients with HTN and 10 transplant donors as controls (CTL) were studied. The glomerular and tubulointerstitial mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction. The corresponding protein level was determined by immunohistochemistry.
Neither the glomerular nor tubulointerstitial mRNA expression of ACE or ACE2 correlated with the corresponding protein level by immunohistochemistry. The tubulointerstitial levels of ACE and ACE2 were significantly lower in HTN than CTL, while the glomerular ACE and ACE2 levels were similar between the groups. The tubulointersitial ACE and ACE2 levels significantly correlated with the estimated glomerular filtration rate (GFR) and inversely with the degree of histological damage. The glomerular ACE and ACE2 levels significantly correlated with the rate of GFR decline. The ratio of glomerular ACE and ACE2 level correlated with the estimated GFR and the degree of glomerulosclerosis.
Our results suggest that intrarenal ACE and ACE2 may play an important role in the pathogenesis and progression of HTN. Studies based on the mRNA expression of ACE and ACE2 should be cautiously interpreted.
Kidney and Blood Pressure Research 02/2011; 34(3):141-9. · 1.46 Impact Factor
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ABSTRACT: The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy. We examined whether urinary expression of specific biomarker mRNA could be used as a noninvasive prognostic marker in kidney transplant recipients.
We studied 63 kidney transplant recipients who require graft biopsy because of progressive worsening of kidney function. The mRNA of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 (KIM-1), IL-18, surfactant protein-C, and S100 calcium-binding proteins A8 and A9 in urinary sediment were quantified.
Urinary expressions of neutrophil gelatinase-associated lipocalin, KIM-1, and IL-18, but not other target genes, were significantly different between histologic groups (P < 0.0001 for all). After followed for an average of 39.7 ± 21.1 months, the rate of renal function decline significantly correlated with urinary KIM-1 expression (r = -0.434, P = 0.0004) but not other target genes. At 48 months, the graft survival rate for the high and low KIM-1 groups were 46.2 and 78.6%, respectively. After adjusting for confounding variables, each log of higher urinary KIM-1 expression conferred an ~2.9-fold higher risk of developing graft failure (95% confidence interval, 1.3- to 6.2-fold; P = 0.006). The result remained similar when only patients with no acute cellular rejection were analyzed.
In kidney allograft recipients, urinary KIM-1 expression provides prognostic information in relation to the rate of renal function decline, irrespective of the kidney pathology.
Clinical Journal of the American Society of Nephrology 12/2010; 5(12):2329-37. · 5.23 Impact Factor
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ABSTRACT: Thin basement membrane disease (TBMD) typically presents with persistent microscopic hematuria, and is usually defined as a glomerular basement membrane (GBM) thickness < 250 nm. Previous studies showed that neither the degree of thinning nor the extent of the abnormality correlate with the patient's clinical presentation or prognosis. To further define this, we enrolled a study group of 41 patients with isolated microscopic hematuria and a normal renal biopsy, except those with a GBM thickness of 250-320 nm, and compared them with 33 patients with traditional TBMD. We found no difference in baseline demographic or clinical parameter between the groups. After follow-up averaging 110 months, there was no significant difference in the risk of detectable or overt proteinuria, hypertension, or impaired renal function between the groups. By the end of the study, only five patients from the study group and four from the TBMD group had no outcome event. By Cox regression analysis, independent predictors of overt proteinuria were male gender, age at biopsy, baseline renal function, proteinuria, and hypertension. Age at biopsy was the only independent predictor for hypertension, and baseline proteinuria was the only independent predictor for impaired renal function. GBM thickness did not predict any outcome event. Hence, lifelong follow-up is advised, as the clinical features and prognosis of these patients with persistent microscopic hematuria and marginally thin GBM are similar to traditional TBMD.
Kidney International 11/2010; 78(10):1041-6. · 6.61 Impact Factor
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Christopher W McIntyre,
Laura E A Harrison,
M Tarek Eldehni,
Helen J Jefferies,
Cheuk-Chun Szeto,
Stephen G John,
Mhairi K Sigrist,
James O Burton,
Daljit Hothi,
Shvan Korsheed,
Paul J Owen, Ka-Bik Lai,
Philip K T Li
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ABSTRACT: Translocated endotoxin derived from intestinal bacteria has a wide range of adverse effects on cardiovascular (CV) structure and function, driving systemic inflammation, atherosclerosis and oxidative stress. This study's aim was to investigate endotoxemia across the spectrum of chronic kidney disease (CKD).
Circulating endotoxin was measured in 249 patients comprising CKD stage 3 to 5 and a comparator cohort of hypertensive patients without significant renal impairment. Patients underwent extended CV assessment, including pulse wave velocity and vascular calcification. Hemodialysis (HD) patients also received detailed echocardiographic-based intradialytic assessments. Patients were followed up for 1 year to assess survival.
Circulating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality.
CKD patients are characteristically exposed to significant endotoxemia. In particular, HD-induced systemic circulatory stress and recurrent regional ischemia may lead to increased endotoxin translocation from the gut. Resultant endotoxemia is associated with systemic inflammation, markers of malnutrition, cardiac injury, and reduced survival. This represents a crucial missing link in understanding the pathophysiology of the grossly elevated CV disease risk in CKD patients, highlighting the potential toxicity of conventional HD and providing a novel set of potential therapeutic strategies to reduce CV mortality in CKD patients.
Clinical Journal of the American Society of Nephrology 09/2010; 6(1):133-41. · 5.23 Impact Factor
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ABSTRACT: Podocyte loss plays an important role in the pathogenesis of diabetic nephropathy, but counting the number of glomerular podocyte in renal biopsy specimen is a labor-intensive task. We study whether intra-renal and urinary messenger RNA expression of podocyte-associated molecules could be used to estimate glomerular podocyte number in patients with diabetic nephropathy.
We studied 21 consecutive patients with biopsy-proven diabetic nephropathy. The intra-renal and urinary mRNA expression of nephrin, podocin, and synaptopodin were measured by real-time quantitative polymerase chain reaction. Podocyte number was determined in micro-dissected glomerulus. The degree of histological scarring was quantified by morphometric analysis.
Glomerular podocyte number correlated with intra-renal expression of nephrin (r=0.510, p=0.044), podocin (r=0.605, p=0.013), and synaptopodin (r=0.480, p=0.060). Glomerular podocyte number also significantly correlated with urinary expression of synaptopodin (r=0.595, p=0.019) but not other targets. Baseline renal function correlated with intra-renal expression of nephrin (r=0.617, p=0.005), synaptopodin (r=0.474, p=0.040), and podocin (r=0.443, p=0.057). The degree of tubulointerstitial scarring also inversely correlated with intra-renal expression of nephrin (r=-0.462, p=0.047), podocin (r=-0.458, p=0.049), and synaptopodin (r=-0.500, p=0.029) but not with urinary gene expression.
Intra-renal expression of podocyte-associated molecules correlated with glomerular podocyte number, renal function, and tubulointerstitial scarring. The results suggest that intra-renal, but not urinary expression of podocyte-associated molecules, might be used to assess the degree of podocyte loss in diabetic nephropathy.
Renal Failure 01/2010; 32(3):372-9. · 0.82 Impact Factor
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ABSTRACT: We studied the role of type 17 Th cells (TH17) in the pathogenesis of SLE.
We quantified the mRNA expression of IL-17, -23, -27 and retinoic-acid-related orphan receptor (ROR)-gamma, the regulator for the development and function of TH17, in the urinary sediment of 23 subjects with active lupus nephritis, 25 subjects with a history of lupus nephritis in remission, 30 SLE patients with no history of renal involvement and 8 healthy subjects.
All three groups of lupus patients had a higher urinary expression of TH17-related cytokines than the controls. However, urinary expression of IL-17 and -27 was found to be inversely correlated with the SLEDAI score (r = -0.252 and -0.258, respectively; P < 0.05 for both). For patients with active lupus nephritis, the histological activity index of kidney biopsy was also found to be inversely correlated with the urinary expression of ROR-gamma (r = -0.447; P = 0.032), IL-17 (r = -0.454; P = 0.029) and IL-23 (r = -0.455; P = 0.029). Urinary expression of IL-17, -23, -27 and ROR was also found to be inversely correlated with the urinary expression of IFN-gamma and T-bet, the key transcription factor of type 1 Th cells. After 6 months of treatment, urinary IL-27 expression rose significantly in patients with complete response (from 2.07 +/- 1.62 to 3.70 +/- 1.69; P = 0.028) but remained unchanged in those with partial or no response (from 2.60 +/- 1.87 to 2.52 +/- 1.94; P = 0.9).
The urinary expression of TH17-related genes is increased in SLE patients. The degree of up-regulation, however, is inversely related to systemic and renal lupus activity, as well as urinary expression of TH1-related genes. Urinary expression of TH17-related genes increased again after successful immunosuppressive treatment of active disease. Our findings suggest a regulatory role of TH17-related cytokines in pathogenesis of lupus nephritis.
Rheumatology (Oxford, England) 09/2009; 48(12):1491-7. · 4.24 Impact Factor
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ABSTRACT: Prolonged sympathetic activation is damaging to the heart and experimental norepinephrine (NE) infusion induces the deposition of myocardial collagen. This study investigated the effects of NE on collagen and transforming growth factor-beta1 (TGF-beta1) gene expression in rat cardiac fibroblasts (CF) culture, and compared the anti-fibrotic effect of alpha and beta (both selective and non-selective adrenergic receptor antagonists) receptors.
Rat CF were cultured in the presence of NE (0.01 to 100 muM) for 24 hours. Procollagen types I and III as well as TGF-beta1 gene expressions were measured by real-time quantitative PCR method. Collagen protein level was measured by Sirius red-based colorimetric method and Western blot analysis. The optimal dose of NE on fibrogenesis was 0.1 muM. Incubation for 24 hours increased procollagen I, III and TGF-beta1 gene expression by 1.35 +/- 0.23, 1.26 +/- 0.16 and 1.35 +/- 0.21 fold, respectively (all p < 0.05). The collagen protein was increased by both Sirius-red assay (0.120 +/- 0.03 vs 0.093 +/- 0.04 microg/total microg of protein, p < 0.05) and Western blot analysis (1.29 +/- 0.26 fold, p < 0.05), when compared with the control group. Addition of carvedilol (a non-selective beta-blocker with alpha-blockage activity) inhibited the effect of NE on procollagen I (0.64 +/- 0.17 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.47 +/- 0.16 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expressions (0.99 +/- 0.12 vs 1.26 +/- 0.31 fold, p < 0.05, respectively). Doxazosin (an alpha-blocker) also inhibited the effect of NE on procollagen I (0.88 +/- 0.30 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.64 +/- 0.13 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expression (0.90 +/- 0.11 vs 1.26 +/- 0.31 fold, p < 0.01 respectively). Such inhibitory effects were not seen in metoprolol (a beta1-selective blocker) and propranolol (a non-selective beta blocker). Furthermore, all the 4 drugs were unable to inhibit the NE induced TGF-beta1 gene over-expression.
In conclusion, NE increased collagen gene and protein expressions in CF culture. This effect is likely mediated through alpha-receptor as they were normalized by pretreatment with carvedilol and doxazosin, but not beta-blockers such as propranolol and metoprolol. Also, TGF-beta1 doesn't seem to play a role in carvedilol inhibition of NE induced fibrogenesis.
Cardiovascular Drugs and Therapy 08/2009; 23(4):271-80. · 3.13 Impact Factor
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ABSTRACT: Podocyte injury probably plays important roles in the pathogenesis of hypertensive nephropathy, but human data are limited. We studied glomerular podocyte count and intrarenal expression of podocyte-associated molecules in patients with hypertensive nephrosclerosis.
We studied 41 consecutive patients with biopsy-proven hypertensive nephropathy, 10 cadaveric kidney donors, and 9 healthy subjects. Intrarenal and urinary mRNA expression of podocyte-associated molecules was quantified and podocyte number was determined by stereological method.
Intrarenal mRNA expression levels of nephrin, podocin, and synaptopodin were lower, and urinary mRNA expression levels were higher in patients with hypertensive nephropathy than controls. Glomerular podocyte number was significantly lower in patients with hypertensive nephrosclerosis than kidney donors (545 +/- 237 vs. 773 +/- 296 per glomeruli, P < 0.02). Podocyte density and intrarenal gene expression of podocyte-associated molecules significantly correlated with estimated glomerular filtration rate (GFR) and inversely correlated with blood pressure and the degree of renal fibrosis. Intrarenal gene expression of nephrin significantly correlated with change in renal function decline.
This study demonstrates a decrease in podocyte number and intrarenal gene expression of podocyte-associated molecules in patients with hypertensive nephrosclerosis. We observed correlations between glomerular podocyte density and intrarenal expression of podocyte-associated molecules with renal function and the degree of renal fibrosis, suggesting podocyte loss may play an important role in the pathogenesis of hypertensive nephrosclerosis.
American Journal of Hypertension 02/2009; 22(3):300-6. · 3.18 Impact Factor
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ABSTRACT: The intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) play important roles in the pathogenesis of diabetic nephropathy, but human data are limited. We studied glomerular and tubulointerstitial mRNA and the protein expression of ACE and ACE2 in patients with diabetic nephropathy.
We studied renal biopsy specimens of 22 patients with diabetic nephropathy and 11 transplant donors as normal controls. Intrarenal mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction; expression at the protein level was determined by immunostaining.
Glomerular and tubulointerstitial mRNA expression levels of ACE and ACE2 were significantly higher in patients with diabetic nephropathy than in normal controls (p < 0.001 for all comparisons). Glomerular ACE and ACE2 protein levels of patients with diabetic nephropathy were significantly higher than those of kidney donors (4.90 +/- 2.55% vs. 2.64 +/- 0.98%, p = 0.022, and 7.40 +/- 3.36% vs. 4.37 +/- 2.36%, p = 0.017, respectively). The tubulointerstitial ACE at the protein level, however, was similar between diabetic patients and controls (8.76 +/- 4.18% vs. 10.44 +/- 6.61%, p = 0.453), and the tubulointerstitial ACE2 at the protein level was significantly lower in diabetic nephropathy (16.48 +/- 7.68% vs. 23.23 +/- 7.65%, p = 0.025).
The mRNA expression of ACE and ACE2 increased in both the glomerular and tubulointerstitial area of diabetic nephropathy. However, the tubulointerstitial ACE expression at the protein level remained unchanged, while that of ACE2 actually decreased. Our results suggest a posttranscriptional modulation of tubulointerstitial ACE and ACE2 expression. Experimental data of intrarenal mRNA expression of ACE and ACE2 should be interpreted with caution.
American Journal of Nephrology 12/2008; 29(6):524-31. · 2.54 Impact Factor
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ABSTRACT: Prolonged sympathetic activation is damaging to the heart. Recent findings suggest that norepinephrine (NE) may contribute to the apoptotic cardiac cell loss. This study investigated high doses NE apoptotic effect on cardiac fibroblasts (CF) culture and compared the anti-apoptotic effect of alpha and beta (selective and non-selective) adrenergic receptor antagonists.
Rat CF were cultured in the presence of NE (1 to 100 microM) for 48 h. bax and bcl(XL) genes expression were measured by real-time quantitative PCR method. Cell viability percentage, apoptotic cell percentage and caspase 3 activity was measured by MTT assay, flow cytometric method and caspase 3 flurogenic assay kit respectively. NE (100 microM) increased bax gene expression by 1.96+/-0.96 fold while bcl(XL) gene decreased by 0.53+/-0.15 fold when compared with the control group (p<0.01). The apoptotic cell percentage increased significantly from 5.09+/-2.94% in control group to 31.48+/-6.35% (p<0.01) with NE and the caspase 3 activity increased from 1432.2+/-658.8 in the control group to 5162+/-2028.6 (OD/microg protein, p<0.05). Addition of carvedilol (non-selective beta blocker with alpha-blockade activity), doxazosin (alpha blocker), metoprolol (beta1 selective blocker) and propranolol (non-selective beta blocker) were not capable of inhibiting the apoptotic effect of high dose NE on CF.
High dose NE has cytotoxic and apoptotic effect on CF. The process involved the activation of caspase 3, up-regulation of pro-apoptotic gene bax and down-regulation of anti-apoptotic gene bcl(XL). Both non-selective and selective adrenergic receptor antagonists tested were not capable of inhibiting the apoptotic effect of high dose NE on CF.
International journal of cardiology 07/2008; 136(1):33-9. · 7.08 Impact Factor
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ABSTRACT: After prolonged peritoneal dialysis (PD) and exposure to a non-physiological dialysis solution, peritoneal mesothelial cells undergo the epithelial-to-mesenchymal transition. In other biological systems, bone morphogenic protein-7 (BMP-7) is a key factor that controls this process. However, the role of BMP-7 in peritoneal physiology has not been studied.
We studied the peritoneal transport characteristics of 50 consecutive new PD patients at 4 and 52 weeks after PD. Peritoneal permeability will be determined by the standard peritoneal equilibration test (PET). BMP-7 in PD effluent (PDE) at mRNA and protein level at 4 weeks was quantified.
At 4 weeks, the mRNA expression of BMP-7 in PDE significantly correlated with peritoneal transport characteristics, including the dialysate-to-plasma creatinine ratio at 4 h (D/P4) (r = 0.422, P = 0.015) and mass transfer area coefficient (MTAC) of creatinine (r = 0.457, P = 0.008). The PDE BMP-7 level by ELISA also had marginal correlation with D/P4 (r = 0.287, P = 0.072) and MTAC creatinine (r = 0.287, P = 0.073), although the result did not reach statistical significance. For the subgroup of patients who remained free of peritonitis, the PDE BMP-7 level by ELISA had significant correlation with the change in D/P4 (r = 0.441, P = 0.017) and MTAC creatinine in 52 weeks (r = 0.415, P = 0.025). The PDE BMP-7 level remained independently associated with the change in peritoneal transport adjusting for age, sex, serum C-reactive protein and PDE transforming growth factor-beta level. In patients who had peritonitis during the study period, the PDE BMP-7 level did not affect the change in peritoneal transport. Conclusion. We find that the peritoneal BMP-7 level correlates with peritoneal transport characteristics, and a high PDE BMP-7 level is associated with a gradual increase in peritoneal transport parameters with time. It remains unclear, however, whether this effect is beneficial, and the therapeutic role of exogenous BMP-7 on peritoneal transport requires a further study.
Nephrology Dialysis Transplantation 05/2008; 23(9):2989-94. · 3.40 Impact Factor
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ABSTRACT: Systemic inflammatory state is a hallmark of peritoneal dialysis (PD) patients, but its etiology remains obscure. Because circulating microbial products are an important cause of systemic immune activation in other conditions such as HIV infection, it was hypothesized that endotoxemia is a cause of systemic inflammatory state and atherosclerosis in PD patients.
Plasma lipopolysaccharide (LPS) levels in 30 consecutive new PD patients were measured. The result was compared with serum C-reactive protein (CRP) level, peritoneal transport status, history of pre-existing cardiovascular diseases, and carotid intima media thickness (IMT) by Doppler ultrasound.
Among the 30 PD patients, there were 17 men. The average age was 53.7 +/- 15.1 yr. The average endotoxin concentration of PD patients was 0.44 +/- 0.18 EU/ml, which was significantly higher than that of patients with chronic kidney disease secondary to Ig-A nephropathy (IgAN) (0.035 +/- 0.009 EU/ml, P < 0.0001) and the controls (0.013 +/- 0.007 EU/ml, P < 0.0001). In PD patients, plasma LPS concentration had a significant correlation with serum CRP (r = 0.415, P = 0.025) and serum albumin level (r = -0.394, P = 0.034). In contrast, plasma LPS level did not correlate with Charlson's Comorbidity Index, peritoneal transport characteristics, or nutritional indices. Patients with pre-existing cardiovascular disease (CVD) had higher plasma LPS level than those without CVD (0.53 +/- 0.19 versus 0.36 +/- 0.16 EU/ml, P = 0.016). Plasma LPS level correlated with carotid IMT (r = 0.438, P = 0.016).
It was found that endotoxemia was probably common in PD patients, and the degree of circulating endotoxemia might be related to the severity of systemic inflammation and features of atherosclerosis. This result suggests that endotoxemia may have a contributory role to the systemic inflammatory state and accelerated atherosclerosis in PD patients.
Clinical Journal of the American Society of Nephrology 04/2008; 3(2):431-6. · 5.23 Impact Factor
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ABSTRACT: Podocyte injury and its subsequent loss in urine play an important role in the pathogenesis of diabetic nephropathy; blockade of the renin-angiotensin system may ameliorate the damage.
In a non-randomized setting, we studied 71 patients with diabetic nephropathy on a stable dose of angiotensin-converting enzyme inhibitor (ACEI). In 37 patients, angiotensin receptor blocker (ARB) was added (the combination group); ACEI alone was continued in the other 34 (the control group). The mRNA expressions of nephrin, podocin, and synaptopodin in urinary sediment were measured at 0 and 12 weeks.
Baseline glomerular filtration rate (GFR) correlated with the urinary expression of nephrin (r=0.320, P=0.007), podocin (r=0.336, P=0.004), and synaptopodin (r=0.350, P=0.003). After adjusting for the baseline expression, the combination group had a significantly lower urinary synaptopodin expression (7.49 (95% confidence interval CI, 0.62-115.29) vs 14.83 (95% CI, 1.03-241.43), P=0.026) than the control group after 12 weeks of treatment. The percentage change in urinary podocin expression over 12 weeks of treatment had a modest correlation with the rate of GFR decline in 1 year (r=-0.243, P=0.041).
In patients with diabetic nephropathy, urinary mRNA expression of podocyte markers correlated with baseline renal function. Urinary expression of synaptopodin was lower after 12 weeks of ACEI and ARB combination therapy. Our result suggests that serial measurement of urinary podocyte markers may have a value for the monitoring of therapeutic response.
European Journal of Endocrinology 04/2008; 158(3):317-22. · 3.42 Impact Factor
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ABSTRACT: To examine urinary expression of podocyte-associated molecules in patients with lupus nephritis (LN).
We studied 32 patients with active LN (Active group) and 17 patients with inactive lupus (Silent group). Messenger RNA expression of nephrin, podocin, and synaptopodin in urinary sediment was quantified by real-time polymerase chain reaction and compared to other clinical measures.
The urinary concentrations of nephrin, podocin, and synaptopodin were significantly higher in the Active than the Silent group (p < 0.05 for all comparisons). There was no relation between urinary gene expression and the histological class of LN, but urinary nephrin expression correlated with proteinuria (r = 0.480, p < 0.01) and the score of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; r = 0.578, p < 0.01). Urinary podocin expression also correlated with SLEDAI score (r = 0.389, p = 0.006). After initiation of immunosuppressive treatment, all patients were followed for an average of 13.7 +/- 2.4 months. The decline of the glomerular filtration rate (GFR) correlated with urinary expression of podocin (r = 0.406, p = 0.005) and synaptopodin (r = 0.337, p = 0.021). In a multiple linear regression model, urinary podocin expression and baseline GFR were independent predictors of GFR decline.
The concentration of podocyte-associated molecules in urinary sediment correlated with lupus activity and GFR decline. The clinical utility of quantifying urinary expression of podocyte-associated molecules for risk stratification of patients with LN deserves further study.
The Journal of Rheumatology 12/2007; 34(12):2358-64. · 3.69 Impact Factor
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ABSTRACT: Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation.
To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis.
36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon gamma (IFN)gamma, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factor beta and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR.
There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNgamma and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNgamma, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3.
Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.
Annals of the Rheumatic Diseases 08/2007; 66(7):886-92. · 8.73 Impact Factor
