Chinese Journal of Nephrology

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Expression of neutrophil extracellular trap and B lymphocyte in renal tissue of patients with lupus nephritis and its significance

LI Min;XING Guang-qun.

2012, 28(4): 267-271.

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Objective To investigate the association of expressions of neutrophil extracellular trap (NET) and B lymphocyte in renal tissue with lupus activity in patients with lupus nephritis (LN). Methods Immunohistochemistry was used to detect the expression of NET (citrullinated histone H3 as the marker) and the infiltration of B lymphocyte (CD19 as the marker) in renal specimens of three groups [LN group, n=20; minimal change disease (MCD) group, n=8; healthy control group, n=3]. The chronic index and SLE-disease activity index (SLE-DAI) in renal tissues of LN and their correlations with NET and B lymphocytes were examined. Results The expression of NET was not found in the renal tissues of healthy control group and MCD group, while it increased significantly in LN group, especially in glomeruli with moderate and severe mesangial cells proliferation, cellular crescents, and tubulointerstitium with inflammatory cell infiltration. Compared with other types of glomeruli, the expression of NET was significantly up-regulated in glomeruli with moderate and severe mesangial cell proliferation(P<0.01). In the glomeruli with moderate and severe glomerular mesangial cell proliferation, the mean number of NET positive cells was positively correlated with renal pathological active index (r=0.620, P=0.004), the score of SLE-DAI (r=0.492, P=0.027) and the mean number of NET positive tubular cells (r=0.558, P=0.011). In renal interstitium, the NET positive cells were positively correlated with CD19 positive B lymphocytes (r=0.573, P=0.008) and renal pathological chronic index(r=0.645, P=0.002). Conclusion NET is widely expressed in the renal tissues of lupus nephritis, which may play a role in the active damage of glomeruli.

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Value of urinary liver-type fatty acid binding protein in prediction of renal function progression in patients with chronic glomerulonephritis

XU Wei-jia;LI Jia-lin;WANG Qin;SHI Bei-li;MOU Shan;NI Zhao-hui.

2012, 28(4): 272-275.

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Objective To evaluate the value of urinary liver-type fatty acid binding protein （L-FABP）as a biomarker in prediction of renal function progression in patients with chronic glomerulonephritis (CGN). Methods A total of 123 patients with newly diagnosed CGN by renal biopsy in Shanghai Renji Hospital between 2004 January and 2005 December were enrolled in the study. Twenty-eight healthy subjects were used as control group. Urine samples were collected before biopsy and treatment, and urinary L-FABP was measured by ELISA. The patients with follow-up every three months for 5 years were divided into progressive group and non-progressive group. The progression of kidney function impairment was defined as a reduction of GFR ≥ 5 ml•min-1•(1.73 m2)-1•year-1 during follow-up. The risk factors of progressive renal function were evaluated and the Spearman correlation analysis was performed to find out the prognostic indicator of renal function deterioration. Results Urinary L-FABP level of CGN patients was significantly higher than that of healthy control group (P<0.01). Urinary L-FABP in CGN patients was negatively correlated with eGFR (r=-0.565, P< 0.01) and positively correlated with proteinuria (r=0.501, P<0.01) and Scr (r=0.601, P<0.01). Kaplan-Meier analysis showed that urinary L-FABP excretion>76.58 μg/g•cr predicted progression of renal function. The AUC of urinary L-FABP for prognosis of CGN progression was 0.95, with 87.5% of sensitivity and 90.5% of specificity at the cutoff value of 119.8 μg/g•cr, which revealed its great value of predicting the prognosis of CGN patients. Conclusion Urinary L-FABP can be a novel biomarker of evaluation for renal injury and early progressive renal function deterioration in patients with CGN.

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Clinical characters of peritoneal dialysis-related staphylococcus peritonitis

TANG Xing-ming;JIANG Zong-pei;YANG Xiao;LIN Jian-xiong;YI Chun-yan;LI Zhi-bin;YU Xue-qing.

2012, 28(4): 276-280.

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Objective To provide evidence for clinical diagnosis and treatment of staphylococcus peritonitis through retrospective analysis of peritoneal dialysis related clinical characters. Methods Patients who experienced staphylococcus peritonitis were observed as peritonitis group. Patients did not experience peritonitis were observed as one-to-one control group in order to investigate predictors of staphylococcus peritonitis, bacteria spectrum, antimicrobial resistance and clinical outcomes. Results There were 74 patients enrolled in either group. For patients in peritonitis group, Kt/V(1.74±0.03 vs 2.61±0.48, P<0.01), CrCL[(55.82±2.22) ml/min vs (76.13±17.42) ml/min, P<0.01], GFR [(1.32±0.55) ml/min vs (3.08±0.75) ml/min, P<0.01], nutrition index, hemoglobin[(91.70±25.43) g/L vs (111.50±19.59) g/L, P<0.01], potassium[(3.43±0.70) mmol/L vs (3.78±0.73) mmol/L, P=0.002], sodium[(137.09±5.06) mmol/L vs (140.57±3.55)mmol/L, P<0.01], chloride[(98.31±6.14) mmol/L vs (101.52±4.58) mmol/L, P=0.001] and calcium [(2.23±0.24) mmol/L vs (2.31±0.22) mmol/L, P=0.04] in serum were significantly lower than those in control group. The morbidity of staphylococcus peritonitis was 0.030 episode per year in recent five years. The major strains were Staphylococcus epidermidis, followed by Staphylococcus aureus. Staphylococci were all sensitive to vancomycin, teicoplanin and linezolid. The cure rate was 89.19%, and mortality was 4.05%. Relapse rate of Staphylococcus epidermidis peritonitis was higher (40%) than other strains. Conclusions Poor nutrition, insufficient dialysis, longer follow-up interval, anemia, electrolytic imbalance are the risk factors of Staphylococcus peritonitis. The morbidity and mortality are lower than before. Staphylococcus epidermidis peritonitis has higher relapse rate and requires more attention to prevention and treatment.

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Association of vitamin D receptor gene BsmI polymorphisms with type 2 diabetic nephropathy

YI Bin;ZHANG Hao;ZHAO Yan;WANG Jian-wen;CAI Xu;LIU Yan;SUN Jian.

2012, 28(4): 281-285.

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Objective To investigate the association between BsmI polymorphism in vitamin D receptor (VDR) gene and diabetic nephropathy in Chinese Han population. Methods PCR-restriction fragment length polymorphism (PCR-RFLP) was used to test the genotype and allele frequency of BsmI in 304 patients with type 2 diabetes mellitus (DM group) and 100 healthy individuals (NC group). The DM group was further divided into non-diabetic nephropathy group (DN0 group, 122 cases), minimal albuminuria group (DN1 group, 87 cases), and mass albuminuria group (DN2 group, 95 cases). Eighty-three DM patients without nephropathy for over 5 years were L-NDN subgroup, and 64 DM patients with nephropathy occurring within the first year were EDN subgroup. Results Genotype and allele frequency of BsmI polymorphism were significantly different between DM and NC group (χ2=7.088, P=0.008; χ2=5.865, P=0.015). BB+Bb genotype and B allele frequency were significantly higher in DN2 group than those in NC group (χ2=14.287, P=0.000; χ2=12.621, P=0.000) and DN0 group (χ2=8.063, P=0.005; χ2=8.173, P=0.004). BB+Bb genotype and B allele frequency were significantly higher in EDN group than those in L-NDN group (χ2=7.228, P=0.007; χ2=5.853, P=0.016). DN patients with allele B (BB and Bb genotypes) presented higher urinary albumin excretion rates compared with patients without allele B (bb genotype, P＜0.01). The genotype of BsmI was correlated with DN, and allele B was risk factor of DN occurrence and early onset (OR=2.004; OR=2.394). Conclusion VDR gene BsmI polymorphism is associated with DN, and the patients carrying allele B are more involved in mass albuminuria and early onset of nephropathy.

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Efficacy and safety of low-protein diet combined with α-keto acids on chronic hepatitis B patients complicated with chronic kidney diseases

LI Jia-lin;YU Zan-zhe;MOU Shan;WANG Qin;SHI Bei-li;NI Zhao-hui.

2012, 28(4): 286-290.

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Objective To evaluate the efficacy and safety of short-term restriction of dietary protein intake (DPI) supplemented with α-keto acids on chronic hepatitis B patients complicated with chronic kidney diseases (CKD). Methods A prospective randomized controlled trial was carried out. Seventeen chronic hepatitis B patients with CKD were randomized to either low DPI with α-keto acid-supplemented (sLP) or low DPI (LP) group for 3 months. Low-protein diet (LPD) was individualized with total energy intake 125.52-146.44 kJ•kg-1•d-1, and protein intake of 0.6-0.8 g•kg-1•d-1. α-keto acid was supplied in a dosage of 0.1 g•kg-1•d-1. Nutritional indexes were recorded and other clinical indexes were measured to evaluate the efficacy and safety respectively. Results The urine protein excretion level and microalbuminuria were significantly decreased at the end of the observation period in the sLP group compared to the basal value and the LP group [24 h urine protein：baseline (4.52±1.74) g, the 1st month (3.19±1.52) g, the 2nd month (2.19±1.1) g，the 3rd month (1.64±0.77) g, P＜0.05; microalbuminyria: baseline (2855.43±248.03) mg/L，the 1st month (2157.14±218.15) mg/L, the 2nd month (1681.57±146.18) mg/L，the 3rd month (924.29±83.33) mg/L, P＜0.05]. No significant difference was found in Scr and eGFR. Nutritional indexes (SGA, serume albumin) were significantly higher at the end of 3 months in the sLP group (P<0.05). No obvious side-effect occurred. Conclusions Short-term restriction of DPI is safe, and when combined with α-keto acids, can increase serum protein and decrease urine protein excretion in chronic hepatitis B patients complicated with CKD without significant side-effect.

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WNK4 kinase-mediated inhibitory effect on expression of BK channel via lysosomal pathway

ZHUANG Jie-qiu;WANG De-xuan;ZHANG Yi-qian;NIU Wei-hui;CHEN Fang-xuan;SHI Zhen;PAN Shu-fang;GU Ding-ying.

2012, 28(4): 291-295.

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Objective To investigate the mechanism underlying the WNK4 kinase-mediated inhibitory effect on BK channel. Methods Cos-7 cells were cotransfected with BK in combination with either CD4 (control group) or wild type WNK4 (WNK4-WT). Immunostaining and confocal microscopy, chemiluminescence, Western blotting analysis were then employed to determine the BK localization in cells, BK surface expression and total protein level, respectively. To further investigate whether the reduction of BK protein expression is due to an increase in degradation through a lysosomal pathway, BK protein level was determined after treated with bafilomycin A1 (Baf A1), a proton pump inhibitor affecting lysosomal degradation. Results Immunostaining and confocal microscopic study showed that BK was localized both in plasma membrane and cytosol in the control group. After cells transfected with WNK4-WT, BK expression was markedly reduced. Chemiluminescent assay found that BK surface expression level was 299.9±18.6 in the control group, whereas it was significantly reduced (148.4±13.7, P<0.01) in the WNK4-WT group. Western blotting analysis showed that total BK protein level was markedly reduced in the presence of WNK4-WT compared to the control group. WNK4-WT was shown to significantly reduce the BK total protein level (42.3%±15.2%) compared to the control group (100%) (P<0.01). When the cells was treated with Bafilomycin A1 (Baf A1, 0.5 μmol/L), WNK4-mediated reduction in BK protein was reversed (82.2%±12.1%, P<0.05). Conclusions WNK4 inhibits total and surface protein expression of BK in Cos-7 cells whick is likely due to an increase in BK degradation through a lysosomal pathway.

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Troglitazone reduces the inhibitory effect of sirolimus on premature 3T3-L1 cell’s function

LI Jin-hong;LI Hang;LIU Ying-jiu;ZHANG Guo-juan;YIN Hong-chao.

2012, 28(4): 296-300.

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Objective To investigate the effects of troglitazone on cholesterol homeostasis and secretion of 3T3-L1 cells by sirolimus and the underlying mechanisms. Methods In vitro cultured 3T3-L1 cells were divided into control group, sirolimus(100 nmol/L) group, sirolimus(100 nmol/L)+ troglitazone(10 μmol/L) group and troglitazone(10 μmol/L) group. High performance liquid chromatography (HPLC) was used to measure intracellular cholesterol accumulation. ELISA was used to measure leptin excretion. Quantitative real-time PCR and Western blotting were used to examine mRNA and protein expression of PPARγ. Results Free cholesterol of sirolimus+ troglitazone group was 1.19 times of sirolimus group (P<0.05). The leptin secretion levels of control group, sirolimus group, sirolimus+troglitazone group and troglitazone group were (19.02±0.52) μg/L, (15.62±0.47) μg/L, (16.45±0.51) μg/L, (18.07±0.66) μg/L，respectively. And the leptin secretion level of sirolimus+ troglitazone group was 1.05 times of sirolimus group(P<0.05). The PPARγ mRNA expressions of sirolimus group, sirolimus+ troglitazone group and troglitazone group were 0.60±0.14, 1.12±0.27, 1.30±0.14 folds of control, and the PPARγ mRNA expression of sirolimus + troglitazone group was higher than that of sirolimus group(P<0.05). PPARγ protein expression had the same tendency. Conclusion Troglitazone reduces the inhibitory effect of sirolimus on PPARγ transactivation and the inhibitory effect of sirolimus on 3T3-L1 cells differentiation and adipogenesis.

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Expression of stem cell factor and infiltration of mast cells in dermal tissue of rats with chronic renal failure

LIANG Yao-xian;LIU Xue-mei;QIU Fang-xin．

2012, 28(4): 301-304.

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Objective To investigate the role of stem cell factor(SCF) and mast cells(MC) in the pathogenesis and progression of dermal lesions caused by chronic renal failure． Methods Thirty-six Wistar rats were randomly divided into model group (adenine lavage at a dose of 150 mg•kg-1•d-1) and control group(physiological saline lavage at equal volume)． Six rats from each group were sacrificed respectively at week 4, 8 and 12． The intensity of MC infiltration was examined by toluidine blue staining. The expression of SCF was detected by immunohistochemistry and real-time fluorescence quantitative PCR． Results Compared with control group, the intensity of MC and the expression of SCF were significantly higher in dermal tissue of model group (P＜0.01, respectively), and they were increased with time． In the model group，the number of MC infiltration was positively correlated with both the protein expression of SCF (r=0.81, P＜0.01) and the level of SCF mRNA (r＝0.65, P＜0.01)． Conclusion The increased SCF and MC may participate in the pathogenesis and progression of dermal lesions caused by chronic renal failure．

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Role of microRNA-215 in nephropathy of type 2 diabetic db/db mice

PANG Qi;MU Jiao;GUO Yan-hong;CHEN Ji-gang;ZENG Wei;HUANG Yong-jun;ZHANG Jun;QIAN Dan;FENG Bing.

2012, 28(4): 305-311.

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Objective To investigate the renal expression changes of microRNA-215 (miR-215) and its role in diabetic nephropathy of type 2 diabetic db/db mice. Methods Four-week-old diabetic db/db mice and normal control group non-diabetic db/m mice were selected. Real-time PCR was used to detect the relative level of miR-215 at the age of 8, 12 and 16 weeks. Catenin beta interacting protein 1 (CTNNBIP1) mRNA and protein level were measured by real-time PCR, Western blotting and immunohistochemisty. A lueiferase reporter assay was used to determine whether CTNNBIP1 was a direct target of miR-215. Results (1)With the growth of db/db mice, the major pathological characteristics of kidney included glomerular hypertrophy, segmental mesangial cells proliferation and mesangial matrix expansion. (2)Compared with the db/m mice, the db/db mice of 8, 12 and 16 weeks showed obvious increase in body weight（BW）, blood glucose (Glu) and 24 hour urinary albumin excretion (UAE) (P<0.05, respectively). (3)Compared with the db/m mice, special miR-215 was highly expressed in the kidney of db/db mice and was up-regulated significantly according to the development of DN (P<0.05). (4)The mRNA and protein expression of CTNNBIP1 of kidney were consistently down-regulated in db/db mice than those in controls(P<0.05, respectively）. (5)By luciferase reporter, miR-215 could negatively regulate CTNNBIP1 gene by targeting its 3’-UTR sequence (P<0.01). Conclusion High expression level of miR-215 plays a potential role in the initiation and progression of DN by down-regulating the expression of CTNNBIP1.

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Syndecan-4 is a candidate gene for diabetic nephropathy

FAN Qiu-ling;LI Sha-li;PU Shi;GUO Jia-yin;YUE Yuan;ZHANG Yu-xia;FENG Jiang-min;MA Jian-fei;JIANG Yi;WANG Li-ning.

2012, 28(4): 312-317.

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Objective To identify the candidate genes in the vicinity of a susceptibility locus(urinary albumin 1, UA-1) contributing to the development of albuminuria in type 2 diabetic KK/Ta mice. Methods Total RNA was extracted from the kidneys of KK/Ta (n=3) and BALB/c (n=2) mice at 20 weeks of age. The gene expression profile in kidney was investigated using the Affymetrix Murine Genome U74Av2 array. Competitive RT-PCR was used to confirm the differential expression of syndecan-4 which located in the vicinity of UA-1. Genome DNA was extracted from KK/Ta and BALB/c mice. DNA sequence analysis of the coding and promotor region of syndecan-4 gene was conducted. Results In the vicinity of the susceptibility locus (UA-1) contributing to the development of albuminuria in type 2 diabetic KK/Ta mice, 10 candidate genes that showed differential expression were identified. Among them, the gene expression of syndecan-4 in KK/Ta kidneys at 20 weeks of age was up-regulated by 26.1 times of age-matched BALB/c kidneys. Sequence analysis revealed two synonymous polymorphisms in the coding region (A93C and T216C) and three polymorphisms in the promoter region (-T263C, -T396C and -G669A) of the syndecan-4 gene. The TATA box was found at 321 bp upstream from the transcription start site, and the T263C polymorphism was located in the binding site of transcription factor Clox. Conclusions Syndecan-4 gene is mapped in the vicinity of the susceptibility locus contributing to the development of albuminuria in type 2 diabetes. The gene expression of syndecan-4 in KK/Ta kidneys is up-regulated than that in age-matched BALB/c kidneys at 20 weeks of age. Thus syndecan-4 may be one of the potential candidate genes responsible for diabetic nephropathy. Sequence differences in the promoter region influence the expression levels of syndecan-4 genes in KK/Ta kidneys.

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Influence of retinoic acid receptor-mediated all-trans retinoic acid on renal tissue cell proliferation and apoptosis in rats with diabetic nephropathy

WANG Yun;CHEN Xiao-lan;CHEN Xu;WANG Na;GUO Nai-feng;FAN Ya-ping.

2012, 28(4): 318-324.

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Objective To investigate the influence of retinoic acid receptor (RAR-α, RAR-β and RAR-γ)-mediated all-trans retinoic acid (ATRA) on renal tissue cell proliferation and apoptosis in rats with diabetic nephropathy, and to analysze the possible mechanism. Methods Male SD rats were randomly divided into normal control group (group N, n=10) and diabetic model group (n=20). Diabetes was induced by streptozotocin(STZ) injection. After successful modeling, the model rats were randomly divided into diabetes group (group D, n=10) and ATRA treatment group (group T, n=10). Rats in group T received ATRA 10 mg•kg-1•d-1 by gavage from the 2nd day of successful modeling for 8 or 12 weeks, meanwhile group N and group D received same volume distilled water. In each group, 5 rats were sacrificed respectively at the 8th week or the 12th week, then biochemical markers were measured and kidney pathology was examined. Apoptosis index(AI) of renal tissue cells of each group was tested by TUNEL. The expressions of RAR-α, RAR-β and RAR-γ in renal tissues were tested using indirect immunofluorescence. The expressions of typeⅠ collagen and laminin as proliferation indicators, along with Smac and caspase-3 as the correlated factors of apoptosis in renal tissue of each group were tested by immunohistochemistry staining. The mRNA expressions of Smac and caspase-3 were tested using real-time fluorescence quantitative PCR. Results Compared with group N, 24 h urine protein, serum creatinine, blood urea nitrogen, ratio of kidney weight/body weight increased significantly (P<0.05, respectively) in group D, and further increased with observation time. Compared with the group D, 24 h urine protein and ratio of kidney weight/body weight decreased in group T (P<0.05, respectively). Compared with group D, the group T presented minor pathological changes. TUNEL assay indicated that compared with group N, the group D showed an obvious increase in renal cell apoptosis in time-dependent manner, and the group T showed a decrease compared with the group D (P<0.01, respectively). Compared with group N, the expression of RAR-α and RAR-β positive cells number in group D were decreased (P<0.01, respectively). Compared with group D, the expression of RAR-α and RAR-β positive cells number in group T increased (P<0.01, respectively). Renal tissues of each group did not show expressions of RAR-γ. After 12 weeks, compared with group N, expressions of type-Ⅰ collagen, laminin, Smac and caspase-3 protein in the glomerular mesangial area and basement membrane of renal tissues in group D increased significantly (P<0.01, respectively), and enhanced with time. Compared with the group D, expressions of typeⅠ collagen, laminin, Smac and caspase-3 protein in group T decreased (P<0.01, respectively). Compared with the group N, group D had an obvious increase in the mRNA expressions of Smac and caspase-3, and a significantly decrease in group T (P<0.01, respectively). Conclusions ATRA may prevent the cell proliferation and apoptosis in diabetic renal tissue through its receptor-mediated pathway, and may protect rats against diabetic nephropathy.

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临床研究

基础研究

临床研究

基础研究