Chinese Journal of Nephrology

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Study on associated protein markers in urine of patients with chronic renal failure

HAO Yi-ming*;HONG Ming-chao;WANG Wen-jing;QIAO Bin;JIN Ya-ming;WANG Yi-qin.

2011, 27(9): 633-636.

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Objective To investigate the associated protein markers in urine of patients with chronic renal failure (CRF) based on surface enhanced laser desorption and ionization time of flight mass spectrometry (SELDI-TOF MS）technique. Methods Urine samples were taken from 150 CRF patients and 50 healthy people, and investigated by proteomic techniques with H4 gene chip. Results Compared to healthy group, 141 different protein peaks were identified within the range of 1000 to 20 000 M/Z in the protein map of CRF group，whose differences were all significant (all P<0.01). The decision tree model for CRF urine was constructed after bioinformation analysis to significantly differentiate between CRF and healthy group. The accuracy rate, sensitivity and specificity of the decision tree model were 96.0%, 100.0% and 94.7% respectively. In CRF group and healthy group, the different protein peaks in urine were identified to probably be 17 proteins with reference to SwissProt database. Conclusions Candidate protein markers in urine are screened and prediction model of CRF urine is established. The markers are identified with the database which provides a more accurate prediction and solid evidence for early diagnosis of CRF.

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Correlation of imbalance of urinary exosome Th1/Th2 with diabetic nephropathy

SUN Ai-li;NI Yi-hong;GUAN Guang-ju;DENG Hao-ping;LIU Yuan-tao;CHEN Shi-hong;SUN Fu-dun;ZHUANG Xiang-hua;HU Xiao-yan;DENG Jing-ti.

2011, 27(9): 637-640.

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Objective To examine the correlation of imbalance of urinary exosome Th1/Th2 with diabetic nephropathy (DN). Methods A total of 120 patients with type 2 diabetes mellitus (DM) and 30 healthy volunteers as control were enrolled in the study. According to urinary albumin/creatinine ratio (UACR), type 2 diabetes mellitus patients were divided into 3 groups: diabetes mellitus without nepbropathy group (DM, n=40, UACR<30 mg/gCr), microalbuminuria group (DN 1, n=50, UACR-30~300 mg/gCr) and clinicoalbuminuria group (DN 2, n=30, UACR＞300 mg/gCr). Urine exosome-interferon-gamma (IFN-γ) and exosome-interleukin 4 (IL-4) levels were determined by enzyme-linked immunosorbent assay (ELISA). Multiple stepwise linear regression was used to analyze the correlation of exosome-IFN-γ/IL-4 with glycated hemoglobin (HbA1c), cholesterol (CH), UACR, Scr and BUN. Results Th1/Th2 ratio in DM, DN1, DN2 groups was significantly higher than that in healthy group (0.8089±0.2458, 0.8993±0.3515, 0.8571±0.2470 vs 0.6198±0.1769, all P<0.01). Correlation analysis showed that urinary exosome-IFN-γ/IL-4 ratio was positively correlated with UACR (r=0.213, P=0.015) and BUN (r=0.292, P=0.001). Multiple stepwise linear regression analysis showed that BUN was independent determinants for exosome-IFN-γ/IL-4 (β=0.246, P=0.006). Conclusion The imbalance of urinary exosome-Th1/Th2 is correlated with DN，which may play an important role in the pathogenesis of DN．

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Effect of energy metabolism on the onset and maintenance of metabolic syndrome in peritoneal dialysis patients

HE Lian; LU Xin-hong;LIU Xia;WANG Tao.

2011, 27(9): 641-645.

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Objective To clarify the association of onset and maintenance of metabolic syndrome (MS) with energy metabolism imbalance, especially with dialysate glucose load in peritoneal dialysis (PD) patients. Methods Using retrospective self-controlled study, the changes of MS, dialysate glucose load and dietary energy intake (DEI) in 126 PD patients in about 1 year were collected and analyzed to define the effect of energy intake on MS. Resting energy expenditure (REE) was measured and physical activity level (PAL) was evaluated based on the activity records in PD patients with unchanged MS state and their impacts on MS were analyzed. Results The incidence of changing from non-MS to MS was higher in glucose load increasing group than that of glucose load unchanged or decreasing group. When glucose load increased, patients developing MS had significantly increased serum triglyceride (TG) level (P<0.01) and significantly decreased serum high density lipoprotein cholesterol (HDL-C) level (P<0.05), while the waist circumference and blood glucose level did not alter significantly. In patients changing from MS to non-MS, their serum C reactive protein (CRP) levels significantly decreased during the follow-up (P<0.05). No significant difference was found in DEI in patients changing from MS to non-MS. However, in patients changing from non-MS to MS, their DEI decreased during the follow up (P<0.05). In a subgroup analysis in 36 PD patients who maintained their metabolic status and did not change their glucose load, there was no difference in REE per body surface per day between the MS group and the non-MS group (t=0.840, P>0.05). However, the PAL was lower in the MS group than that of the non-MS group (t=2.358, P<0.05). Conclusions The increase of dialysate glucose load may be an important factor leading to the onset of MS, by altering serum TG and HDL-C level. Inflammation and the sedentary life also contribute to the MS state.

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Correlation of Notch1 receptor expression in renal tissue of hepatitis B virus associated-glomerulonephritis with clinicopathology

ZHOU Yi;ZHU Nan;YUAN Wei-jie;SHANG Ming-hua;LIU Jun;WANG Ling;GU Li-jie.

2011, 27(9): 646-651.

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Objective To investigate the expression of Notch1 receptor in renal tissues of patients with hepatitis B virus associated-glomerulonephritis (HBV-GN) and its role in the pathogenesis of HBV-GN. Methods A total of 48 patients with HBV-GN confirmed by renal biopsy during 2008-2010 were enrolled in the study. Distribution of Notch1 receptor in renal tissue of HBV-GN was detected by immunohistochemistry and the association between the distribution of Notch1 receptor and HBsAg was examined by double-label immunofluorescence assays. Correlations of Notch1 receptor expression with renal pathology and clinical parameters of HBV-GN were analyzed. Results Notch1 receptor distributed mainly in renal tubular epithelial cells and interstitial area as brownish red granules, and a few expression in glomerulus was also found. The positive score of Notch1 receptor expression in HBV-GN patients was significantly higher as compared to primary glomerulonephritis patients with serum HBsAg positive or negative and normal renal tissue controls. Notch1 receptor expression was more obvious in membrano-proliferative glomerulonephritis (MPGN) and mesangial proliferative nephritis (MsPGN) patients, but there was no significant difference among the different pathology groups. Distribution of Notch1 receptor was consistent with the distribution of HBsAg and its intensity was positively correlated with renal interstitial fibrosis (r=0.473, P=0.001), tubular atrophy (r=0.690, P=0.000), inflammatory cell infiltration (r=0.616, P=0.000). Negative correlation was found between renal function and the intensity of Notch1 receptor (r=-0.393, P=0.006). Conclusions Notch1 receptor expression increases in the renal tissues of HBV-GN patients and distributes mainly in renal tubular epithelial cells and interstitium, which is consistent with the distribution of HBsAg. Its intensity is closely correlated with renal interstitial lesions and renal function. Abnormal expression of Notch1 receptor in renal tissue of HBV-GN may be involved in the progress of HBV-GN.

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Efficacy of imipenem-cilastin sodium as subsequent therapy on peritoneal dialysis-related peritonitis

SHI Jun-bao;NIE Jian-dong;SUN Ling-hua;FU Gang;HAN Qing-feng.

2011, 27(9): 652-655.

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Objective To evaluate the efficacy of imipenem-cilastin sodium as subsequent therapy on peritoneal dialysis(PD)-related peritonitis. Methods From January 2007 to December 2010, 44 PD-related peritonitis patients in our hospital were enrolled in the study. These patients presented cloudy fluid after 3 days initial treatment, and bacterial culture was Gram-negative bacteria or negative. Thirteen peritonitis episodes were treated with ceftazidime, while 36 episodes with imipenem-cilastin sodium. Efficacy, outcome, pathogen and drug-resistance were analyzed retrospectively. Results The effective rates 2 d later of ceftazidime and imipenem-cilastin sodium were 23.1% and 72.2% respectively with significant difference (P<0.05). Gram-negative bacteria of ceftazidime and imipenem-cilastin sodium groups were 69.4% and 65.2% respectively without significant difference (P>0.05). The cure rates 3 weeks later of ceftazidime and imipenem-cilastin sodium groups were 23.1% and 72.2% respectively with significant difference (P<0.05). Conclusion As subsequent therapy for PD-related peritonitis, imipenem-cilastin sodium can improve the cure rate.

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Proteolytic system is dysfunctional in diabetic nephropathy model rats

LI Zhi-guo;ZHANG Hao-jun;DONG Xi;WANG Hong-pan;YANG Fang;SHEN Hong;LI Ping.

2011, 27(9): 656-661.

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Objective To investigate autophagy and proteasome system alteration in vivo and in vitro of diabetic nephropathy (DN) model rats. Methods Rat glomerular mesangial cells were primaryly cultured, and cell proliferation was tested by MTT assay. The mesangial cells were cultured under different concentrations of glucose (5.4 mmol/L for normal control and 30 mmol/L for high glucose) for 0, 8, 16, 72 hours. The expression of autophagy (LC3) and proteasome (PSMAs) proteins was examined by Western blotting analysis. Spontaneous type 2 diabetes model OLETF and its normal control LETO rats were observed for 36 weeks. The levels of blood glucose and 24 hours urinary protein were evaluated in every 4 weeks. All the rats were sacrificed at the 36th week, and renal pathological changes were semi-quantitively analyzed. The expression of PSMAs and LC3 proteins was also examined in kidney cortex by Western blotting. Results Under high glucose concentrations, the abundance of PSMAs and LC3 proteins significantly reduced in the mesangial cells at 8 hours. There was no significant difference at other time points. The levels of blood glucose and 24 h urinary protein in OLETF rats exhibited progressive increase compared to those in LETO rats(all P<0.01). And glomerular sclerosis index and tubulointerstitial injury index were significantly higher than those in LETO rats (all P<0.01). The abundance of PSMAs proteins was significantly reduced in renal cortex of OLETF rats compared with LETO rats, while the abundance of LC3 proteins had no significant difference between two groups. Conclusion Proteolytic system dysfunction may play a role in pathogenesis of DN.

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Effect of soluble Tie2 fusion protein on peritoneal angiogenesis in uremic peritoneal dialysis rats

ZHAO Zhan-zheng;LIU Xin-xin;LI Zhen-zhen;SHEN Wan-qin;XIAO Jing;WU Ge;TANG Lin;XING Guo-lan;LIU Zhang-suo.

2011, 27(9): 662-666.

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Objective To investigate the effect of soluble Tie2 fusion protein(sTie2/Fc) on the angiogenesis of peritoneal vessels in uremic peritoneal dialysis (PD) rats. Methods Rats were randomly divided into 6 groups: normal rats as control group (group1), rats with sham operation (group2), uremic rats without PD (group3), uremic rats dialyzed with 4.25% PD solution (group4), uremic rats dialyzed with 4.25% PD solution and treated by subcutaneous injection of 2.5 μg/kg sTie2/Fc (group5), uremic rats dialyzed with 4.25% PD solution and treated by subcutaneous injection of 5.0 μg/kg sTie2/Fc (group6). sTie2/Fc was given every other day during peritoneal dialysis period, total 14 doses. After regular PD for 28 days, RT-PCR and tissue immunohistochemical staining were used to detect the mRNA and protein expressions of Angpt-2 in peritoneal tissues in each group of rats. Microvessel density (MVD) of peritoneum was detected and quantified with immunohistochemical staining by using anti-CD34 antibody. Results The expression of Angpt-2 mRNA and protein was found in each group. There was no significant difference of Angpt-2 expression both in mRNA and protein level between group1 and group2. Compared with group1, the mRNA and protein expression of Angpt-2 were significantly increased in group3 and group4(all P<0.05). Compared with group3, the mRNA and protein expression of Angpt-2 were significantly increased in group4(all P<0.05). Compared with group 4, the mRNA and protein expression of Angpt-2 were significantly decreased in group5 and group6 (all P<0.05). Compared with group5, the mRNA and protein expression of Angpt-2 were significantly decreased in group6(all P<0.05). Only few new microvessel was found in group1 and group2. Compared with group1, MVD was significantly up-regulated in group3 and group4(all P<0.05). Compared with group4, MVD was significantly down-regulated in group5 and group6(all P<0.05). Conclusions Peritoneum neoangiogensis can be effectively inhibited by sTie2/Fc in uremic rat treated with PD. Blocking of signal transduction may be involved in the mechanism of sTie2/Fc inhibiting peritoneal angiogenesis.

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Role of renin-angiotensin system in advanced glycation end products-induced changes of permeability in rat glomerular endothelial cells

LI Can-ming;YE Zeng-chun;PENG Hui;LUO Peng-li;LAI Wei-yan;LI Ming;LOU Tan-qi.

2011, 27(9): 667-672.

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Objective To investigate the effect of advanced glycation end products (AGEs) on the disruption of tight junctions in rat glomerular endothelial cells (rGEnCs) and the role of renin-angiotensin system(RAS) in this pathological procedure. Methods Primary cultured rGEnCs were incubated with AGEs at concentrations of 20 mg/L, 40 mg/L and 80 mg/L, for 6 h, 12 h and 24 h respectively. The cells were treated with captopril (1 mmol/L) or valsartan (10 μmol/L) to block RAS. The endothelial permeability was investigated by transendothelial electrical resistance and the flux of fluorescein isothiocyanate-conjugated bovine serum albumin. The expression of AGEs receptor(RAGE), tight junction proteins [occludin, claudin-5, junctional adhesion molecules A (JAM-A) and zona occludens-1(ZO-1)] and RAS components [angiotensinogen, renin and angiotensinⅡ type 1 receptor(AT1)] were detected by Western blotting. Immunofluorescence was used to demonstrate the disruptions of the tight junction proteins. The activity of angiotensin converting enzyme(ACE) was evaluated by UV spectrophotometry. Angiotensin Ⅱ(AngⅡ) was measured by enzyme immunoassay. Results The monolayer permeability, the expression of RAGE, the activity of ACE, the concentration of AngⅡ and the expression of AT1 of rGEnCs were increased after induced by AGEs. Meanwhile, AGEs decreased the expression of occludin, claudin-5 and JAM-A and induced disruption of tight junction proteins. Pretreatment with anti-RAGE antibody(100 mg/L), captopril or valsartan could attenuate the detrimental effect of AGEs. Conclusion The changes of permeability induced by AGEs in glomerular endothelial cells are partly mediated by RAS through RAGE.

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Role of NF-κB in the progression of aldosterone-induced renal injury and its associated mechanisms

YANG Lei;DING Wei;ZHANG Min-min;GU Yong.

2011, 27(9): 673-677.

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Objective To investigate the role of NF-κB in aldosterone-1%NaCl-induced renal injury in uninephrectimized SD rats and the potential mechanisms. Methods Thirty-teo male SD rats were uninephrectomized and treated for 4 weeks. Rats were divided into four groups randomly: control group (n=8), 1%NaCl group (1%NaCl in chow, n=8), aldosterone group (1%NaCl in chow, 0.75 μg/h aldosterone delayed relase by osmotic mini-pump, SC, n=8), PDTC group (1%NaCl in chow, 0.75 μg/h aldosterone, SC, 100 mg/kg PDTC, IG, n=8). Systolic blood pressure (SBP), urinary protein, renal function and renal morphologic were observed. The expression of intercellular cell adhesion molecule 1(ICAM-1) and connective tissue growth factor (CTGF) were measured respectively by Western blotting and real-time PCR. The activity and location of NF-κB in renal cortex were detected by electrophoretic mobility shift assay(EMSA) and immunohistochemisty. Results Rats of aldosterone group exhibited higher blood pressure and more serious renal injury characterized by proteinuria, glomerular sclerosis compared with rats of the 1%NaCl group. Protein and mRNA levels of ICAM-1 and CTGF were significantly increased in aldosterone group rats than those in 1%NaCl group (all P<0.05). Moreover, all these changes were associated with an increase in NF-κB activity. Treatment with PDTC which is a specific inhibitor of NF-κB notably alleviated SBP, proteinuria and renal injury in aldosterone-infused rats. Furthermore, PDTC markedly reduced the expression of ICAM-1 and CTGF(all P<0.05). Conclusion PDTC can alleviate aldosterone-1%NaCl-induced renal injury in uninephrectimized SD rats by preventing the expression of ICAM-1 and CTGF.

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Effects of intermedin pretreatment on associated repairing genes in the kidney of rats with renal ischemia-reperfusion injury

ZHAO Li;LI Rong-shan;QIAO Xi;ZHAO Hai-hong;LIU Xin-yan;SHAO Shan.

2011, 27(9): 678-683.

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Objective To investigate the effects of intermedin (IMD) pretreatment on associated repairing genes of the rats with injured kidneys by ischemia reperfusion injury (IRI) during the repair and regeneration process. Methods A total of 144 healthy male Wistar rats were randomly divided into 4 gourps: sham opration group, IRI group, empty plasmid group (EP) and IMD group. After resection of right kidneys of the rats, plasmid was transfected into the left kidneys by using ultrasonic microbubble technology. After one week, the renal IRI models were programmed. The samples of renal tissues after 1 d, 2 d, 3 d, 4 d, 7 d and 14 d of reperfusion were harvested respectively, then the mRNA expressions of the Pax-2, ZO-1, Ncam, Wt-1 and vimentin in renal tissues were detected by RT-PCR; the protein expressions of Pax-2, Wt-1 and vimentin were analyzed by Western blotting and the protein expressions of ZO-1 and Ncam were measured by ELISIA. Results (1) Compared with the sham group, the mRNA and protein expression of Pax-2, ZO-1, Ncam, Wt-1 and vimentin of the rats in IRI group increased significantly from day 1 to day 3 (P<0.05), which peaked at day 2. After day 4, the above expressions in IRI group returned to normal level. (2) In IMD group, the mRNA and protein expressions of Pax-2, Zo-1, Ncam, Wt-1 and vimentin were significantly higher than those in other 3 groups (P<0.05) at the same time after IRI day 1 to day 4, with a maximum in day 2. (3) The above expressions in IRI group, EP group, IMD group had no significant differences compared with sham group after day 7 or day 14 respectively(P>0.05), and either between IRI group and EP group, though the expressions of the genes in IRI group and EP group increased compared with sham group after day 4. (4) The above expressions between IRI group and EP group also had no significant difference (P>0.05). (5) Changes of ZO-1 and Ncam protein expression detected by ELISA were similar to those abore mRNA and protein expression by RT-PCR and Western blotting. Conclusion IMD pretreatment plays an important role in up-regulation of the expressions of associated repair genes during the process of repair and regeneration after renal ischemia reperfusion injury.

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Different impacts of subtotal nephrectomy and ischemia-reperfusion injury on renal stem cells and progenitor cells of rats and their significance for renal prognosis

LIU Jun-min;ZHANG Xin-zhou;ZHANG Wan-fan;HE Xiao-lei;DAI Yong;WU Yao-jiong.

2011, 27(9): 684-691.

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Objective To compare the impacts of subtotal nephrectomy and ischemia-reperfusion injury on renal stem cells and progenitor cells of rats, and to explore the significance of renal stem cells and progenitor cells for renal repair and the possible mechanisms of prognosis in rats with acute renal failure（ARF） or chronic renal failure (CRF). Methods Rats of CRF or ARF model underwent 5/6 nephrectomy or renal artery ligation and reperfusion respectively, and rats in control group underwent sham operation. Scr, BUN and 24 hour urine protein were regularly measured. Kidney specimens were obtained at the set time for HE staining and fluorescence staining. Expressions of CD24, CD133 and podocin were detected by immunofluorescence. RT-PCR was performed to quantify the expression of transforming growth factor β1 (TGF-β1), Notch2, hepatocyte growth factor (HGF), bone morphogenetic protein 7(BMP7) and Pax-2 mRNA in renal tissue and the expression of podocin mRNA in renal cortex. Correlation among the expressions of Pax-2 mRNA, podocin mRNA and glomerulosclerosis index were analyzed. Results The rats of two models presented typical ARF or CRF in renal pathology and function. Glomerulosclerosis index in CRF group increased gradually with time, which were (2.34±0.28)%, (25.12±5.67)%, (89.42±12.28)% and (171.23±32.28)% at day 14, day 30, day 60 and day 90 respectively. Compared with sham group, the CD24+CD133+ cells of the ARF rats showed no significant change in quantity and distribution, while the CRF rats showed gradual reduction of CD24+CD133+ cells. The expression of podocin in glomerulus decreased temporarily and recovered finally after ischemia-reperfusion injury, but decreased gradually after 5/6 nephrectomy. Compared with sham group, expression of TGF-β1, Notch2 mRNA in renal tissue was increased in CRF group, while the expression of HGF, BMP7 mRNA in renal tissue of ARF group were increased. Between the expression of Pax-2 mRNA in renal tissue and the expression of podocin mRNA in renal cortex, there was positive correlation in CRF group, while they both were negatively correlated with glomerulosclerosis index. Conclusions Ischemia-reperfusion injury makes no obvious impairment to renal progenitor cells. Having progressively injured the living environment of renal progenitor cells, subtotal nephrectomy reduces renal progenitor cells, and causes podocytes to repairing incompetently, which may be the main pathogenesis of CRF with poor prognosis.

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基础研究

临床研究

基础研究