Chinese Journal of Nephrology

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Effect of tacrolimus on macrophage accumulation, proliferation and activation in the kidney of early diabetic rats

SU Shuang-quan;ZHAO Li;XIA Lin;HU Mei-fen;WU Yong-gui.

2012, 28(7): 507-511.

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Objective To investigate the effect of tacrolimus(FK506) on macrophage accumulation，proliferation and activation in the kidney of early diabetic rats and to explore its possible mechanism of renal protection． Methods Rats were randomly divided into control, model and tacrolimus groups. Diabetic model rats were induced with intraperitoneal injection of streptozotocin. Tacrolimus (0.5 or 1.0 mg•kg-1•d-1) was orally administered once a day for 4 weeks. Kidney weight index (KWI), 24-h urinary albumin excretion rate (UAER) and creatinine clearance rate (Ccr) were measured. Kidney pathology was observed by light microscopy. ED-1, PCNA and iNOS positive macrophages were detected by single and double staining of immunohistochemistry. Results KWI increased in model group and was significantly reduced by tacrolimus treatment with 1.0 mg•kg-1•d-1(P<0.05). UAER elevated in model group and was markedly attenuated by tacrolimus treatment with 0.5 and 1.0 mg•kg-1•d-1(P<0.05). Elevated glomerular volume of model rats was significantly decreased by tacrolimus treatment with 0.5 and 1.0 mg•kg-1•d-1(P<0.05), and increased indices of tubulointerstitial injury were only ameliorated by 1.0 mg•kg-1•d-1 tacrolimus (P<0.01). Marked accumulation of ED-1+ cells in diabetic kidney was found, which was not inhibited by tacrolimus treatment with 0.5 and 1.0 mg•kg-1•d-1. ED-1+ PCNA+ cells and ED-1+ iNOS+ cells were significantly elevated in kidneys of model group, while they were significantly inhibited by tacrolimus treatment with 0.5 and 1.0 mg•kg-1•d-1(P<0.01). Conclusion Tacrolimus can ameliorate early renal injury of diabetic rats and its mechanism may be partly associated with the suppression of increased macrophages activation.

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Impact of spironolactone on the expression and activity of ROCK1 in renal tissues of uninephrectomized diabetic rats

WANG Dan;SHI Hui;FAN Ya-ping;JIANG Xin.

2012, 28(7): 512-517.

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Objective To investigate the expression and activity of Rho-associated kinase 1 (ROCK1) in renal tissues of uninephrectomized diabetic rats, and to explore the possible mechanism of renal protection of spironolactone. Methods The model rats were established by a single intraperitoneal injection of streptozotocin (STZ) after uninephrectomy and randomly divided into sham operation group (N), uninephrectomized control group (C), uninephrectomized diabetic group (D), and spironolactone treated group (S). Four and 8 weeks later, biochemical indexes and renal morphology were detected. Expressions of ROCK1 and connect tissue growth factor (CTGF) were examined by immunohistochemistry and real-time PCR. Protein expression of p-MYPT1 was examined by Western blotting. Results After 4 and 8 weeks, compared with group N and C, blood glucose, systolic blood pressure, 24-h urinary protein, kidney weight/body weight (KWI) were significantly increased(P<0.01), and extracellular matrix proliferation and basement membrane thickening were found in group D. After 8 weeks in group D, Alb significantly decreased and Scr significantly increased(P<0.05). In group D, protein and mRNA expression of ROCK1 and CTGF increased significantly and protein expression of p-MYPT1 increased significantly as well with time. Treatment with spironolactone could partially reverse those changes. Conclusions Expression and activity of ROCK1 increase in renal tissues of uninephrectomized diabetic rats and are positively correlated with the expression of CTGF. Spironolactone can protect the kidney of diabetic rats in early stage probably through decreasing the expression of ROCK1, CTGF and inhibiting the activation of ROCK1.

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Renal protective effect of lentivirus-mediated adiponectin gene transfection on streptozocin-induced early diabetic nephropathy mice

SU Yan-xin;DENG Hua-cong;LONG Jian;ZHANG Ming-xiang;PENG Zhou-gui.

2012, 28(7): 518-523.

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Objective To investigate the renal protective effect of recombinant lentivirus encoding adiponectin gene on streptozocin-induced early diabetic nephropathy (DN) mice, and to explore its potential mechanism. Methods Forty C57BL/6 mice were randomly divided into normal control group (NC group, n=10), diabetic nephropathy group (DN group, n=10), Lenti-IRES-EGFP treatment group (DL group, n=10) and Lenti-Acdc-IRES-EGFP treatment group (DA group, n=10). After 8 weeks of recombinant lentivirus injection, kidney to body weight ratio (KW/BW), mean glomerular volume (MGV), fractional mesangial area (FMA), 24 h urinary protein excretion (UTP), Scr, BUN, serum albumin and adiponectin were measured. Renal pathological changes were evaluated by electron microscopy. Proliferation of glomerular and tubulointerstitial cells was assessed by immunohistochemistry using PCNA antibody. The phosphorylation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin protein (mTOR) were detected by Western blotting. Results Adiponectin was successfully over-expressed in STZ-induced DN mice after lentivirus injection. KW/BW, MGV, FMA and UTP were significantly decreased in DA group as compared to DN group and DL group (P<0.05), but were increased as compared to NC group (P<0.05). DA group animals had significantly fewer PCNA-positive cells than DN group and DL group (P<0.01). DA group mice had higher p-AMPK level and lower p-mTOR level as compared to DN group and DL group (P<0.01). Conclusion Over-expression of adiponectin has beneficial effect on early DN and attenuates aberrant proliferation of renal cells via AMPK-mTOR pathway.

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Impact of paricalcitol on proteinuria in diabetic nephropathy rats

LAN Kai;LUO Qun;ZHOU Fang-fang;WU Min-xiang;CAI Ke-dan.

2012, 28(7): 524-527.

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Objective To study the effect of 1,25-(OH)2D3 analogs paricalcitol on proteinuria in diabetic nephropathy (DN) rats, and to investigate its possible mechanism. Methods DN model rats were established by intraperitoneal injection with streptozotocin. All the DN rats were randomly divided into the paricalcitol group (group P ) and DN group (group D). Healthy rats were chosen as healthy control group (group N). 24-h urinary protein and serum biochemical indicators were examined after 12 weeks. ELISA was applied to detect the level of renin and AngⅡ in the kidney. Immunohistochemistry and real-time PCR were used to detect the protein and mRNA expression of heparanases (HPA）and podocin. Results Compared with group N, 24-h urinary protein, serum creatinine, renin and AngⅡ in group D and group P were markedly increased, and they were significantly higher in group D as compared to group P (all P<0.05). Compared with group N, the expression of HPA protein and mRNA in group D and group P increased markedly, and higher expression was found in group D (all P<0.05). The expression of podocin protein and mRNA in group D and group P decreased markedly, and lower expression was found in group D (all P<0.05). Renin level was positively correlated with HPA protein expression (r=0.78, P<0.05)，negatively correlated with podocin protein expression (r=-0.63, P<0.05), and not correlated with their mRNA expression. Conclusion Paricalcitol can significantly reduce the proteinuria, which may be associated with the inhibition of renin by down-regulating protein expression of HPA in glomerular basement membrane and up-regulating protein expression of podocin in podocyte.

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Epidemiology investigation on rheumatoid arthritis and chronic kidney disease among population older than 45 years in Luohe city

SUN Jian;LIU Dong-wei;LIU Zhang-suo.

2012, 28(7): 534-537.

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Objective To study the prevalence of chronic kidney disease (CKD) among population with rheumatoid arthritis(RA) in Luohe city. Methods 3072 residents (older than 45 years) with eligible data from Luohe city were randomly selected using a stratified, multistage sampling. All residents were interviewed and given physical examination, tested for sample of uria and blood, and also given special examination about RA. Results The prevalence of RA was 6.90% in 3072 subjects. The albuminuria was detected in 10.42% of subjects, hematuria in 8.59%, reduced renal function in 1.82%, Howerer, which was higher in patients with RA, was 14.62%, 10.85% and 4.72% respectively. Especially the prevalence of albuminuria and reduced renal function in RA patients was significantly higher compared to that in population without RA(14.62% vs 10.10%, P＜0.05 and 4.72% vs 1.61%, P＜0.01), but no significant differences in hematuria(10.85% vs 8.43%, P＞0.05). The prevalence of CKD was 16.93% in tougher, and RA patients had higher prevalence of CKD than those population without RA(22.17% vs 16.54%, P＜0.05). Conclusion The prevalence of CKD among population older than 45 years in Luohe city is high, and the patients with RA have special characteristic in epidemiology of CKD.

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Could serum cystatin C be employed in diagnosing contrast-induced nephropathy after non-emergency endovascular therapy with peripheral arterial diseases?

YANG Yan-jiao;TANG Xiao;ZHOU Ying;ZHENG Yin;CHEN Ying-ying;GUO Da-qiao;DING Feng.

2012, 28(7): 538-543.

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Objective To investigate the risk factors for contrast-induced nephropathy(CIN) after endovascular therapy in patients with peripheral arterial diseases and to evaluate the conformance of serum cystatin C (Cys C) and serum creatinine in diagnosis of CIN. Methods In this prospective, single center study, in-hospital patients with peripheral arterial diseases undergoing non-emergency endovascular therapy from July 2010 to April 2011 in our hospital were enrolled. CIN was defined as Scr increase≥25% after angiography. General clinical characteristics and blood biochemical parameters were compared between the non-CIN and CIN groups. Logistic regression analysis was performed to determine risk factors. Changes compared to baseline level in serum creatinine and Cys C at predefined time-points were evaluated. Results A total of 367 patients were enrolled in the study. The proportions of patients with diabetes mellitus and treatment with diuretics before angiography, contrast-media dosage were significantly higher in the CIN group than those in non-CIN group(P＜0.05, ＜0.01, ＜0.01). Logistic regression analysis indicated that diabetes mellitus, contrast-media dosage were risk factors for CIN. Several serum Cys C increase criteria at 24 hours after contrast media exposure all had low sensitivity for predicting a Scr increase≥25%. Only small overlapped regions were found in Venn diagram between several increasing criteria according to serum Cys C and serum creatinine criterion. Conclusions Diabetes mellitus, contrast-media dosage are independent risk factors for CIN. The results of several increasing criteria according to serum Cys C in evaluating contrast-induced AKI are not coincident well with that of serum creatinine criterion.

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Role of anti-podocyte antibody in the pathogenesis of membranous nephropathy

LI Juan;YAN Li-jing;YANG Lin.

2012, 28(7): 544-547.

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Objective To investigate the role of the anti-podocyte antibody in the pathogenesis of membranous nephropathy (MN). Methods Thirty-six frozen section slice from biopsies of normal kidney were randomly divided into 3 groups: A, B and C groups (n=12, respectively), then, serum of MN and IgA nephropothy patients, and normal saline were added by drops to frozen section respectively, then the changes were observed by fluorescence microscope. Twenty-one male New Zealand white rabbits were feed with standard diet for 1 week, then were randomly divided into 3 groups: D, E, F groups (n=7, respectively), and injected with the serum of MN and IgA nephropathy, and normal saline respectively through ear-border vein. 24-h urinary protein, serum albumin, serum creatinine were detected. At week 8 after injection, the histopathological changes in kidney tissue of rabbits were observed by light microscope, electron microscope and immunofluorescence staining. Results Immunofluorescence staining displayed IgG deposition in glomerular podocytes in group A, and there was no positive expression in other two groups. The quantitative measurement of 24-h urinary protein increased significantly after injection of MN serum (P<0.01), meanwhile the serum albumin markedly decreased (P<0.01). The immunofluorescence staining showed that IgG deposited in the glomerulus capillaries wall, which presented spherical particles. Light microscope revealed the thickening of GBM without nailing process formation. Electron microscope showed the podocyte foot processes, subepithelial dense deposits. Such pathological changes were not found in E group and F group. Conclusion There is anti-podocyte antibody in blood of MN patients, which may play a role in the pathogenesis of MN.

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Angiotensin Ⅱ induces podocyte c-Abl expression change

CHEN Xing-hua;REN Zhi-long;MA Te-an;ZHA Dong-qing;CHEN Cheng;DING Guo-hua．

2012, 28(7): 548-552.

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Objective To evaluate the effects of angiotensin Ⅱ(AngⅡ)infusion on renal c-Abl expression in vivo, and on podocyte c-Abl expression change in cultured mouse podocytes. Methods Twenty four male Sprague-Dawley rats(Group C, D, E and F) were assigned to receive Ang Ⅱ (400 ng•kg-1•min-1) by osmotic minipump and of which 12 rats(Group D and F) were assigned to receive telmisartan (3 mg•kg-1•d-1), six rats received normal saline(Group B), and six rats were used as normal contro1 (Group A). Animals were sacrificed at day 14(Group C and D), day 28(Group E and F) respectively. Conditionally immortalized mouse podocytes were used in vitro. Podocytes were studied 2 weeks after thermoswitching from 33℃ to 37℃. Cells were fetal bovine serum (FBS) starved for at least 12 hours prior to stimulation. The cultured podocytes were treated with Ang Ⅱ doses ranging from 10-9 mol/L to 10-6 mol/L and for different hours. Expression of renal and podocytes c-Abl was examined by immunofluorescence staining, real-time PCR and Western blotting. Results (1) Distribution of c-Abl expression was mainly in the cytoplasm and nuclear of the podocytes in vivo and in vitro. (2) Expressions of c-Abl mRNA and protein were increased in AngⅡ-infused rat podocytes and AngⅡ-induced cultured mouse podocytes (P＜0.05), and the effects of AngⅡ were dose-dependent and time-dependent in vitro. Conclusion There are c-Abl mRNA and protein expression in podocytes, and c-Abl may play a critical role in the pathogenesis of AngⅡ-induced podocyte injury.

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Effect of ceramide on peritoneal mesothelial cells apoptosis induced by peritoneal dialysis solution

TANG Tian-feng;WANG Bin;ZHANG Miao;JIANG Chun-ming;SUN Cheng.

2012, 28(7): 553-557.

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Objective To explore the effect of ceremide on process of peritoneal mesothelial cells(PMCs) apoptosis induced by peritoneal dialysis solution(PDS). Methods PMCs were cultured with normal DMEM, 1.5% PDS and 4.25% PDS. 4.25% mannitol was used as high osmotic pressure control. Ceremide were detected by LC-MS-MS. Flow cytometry was used in apoptosis analysis. Bax, p53 and bcl-2 protein expressions were detected by Western blotting. Results (1) PDS caused the increase of intracellular ceremide in PMCs, and normal and high osmotic pressure controls had no such effect. As the acidic sphigomyelinase inhibitor, desipramine significantly inhibited the production of ceramide induced by 4.25% PDS[(56.08±12.24) μg/L vs (91.25±15.89) μg/L, P<0.01]. (2) Compared with 1.5% PDS, 4.25% PDS stimulated PMCs apoptosis(26.65%±6.21% vs 4.04%±1.86%, P<0.01), up-regulated bax and p53 proteins expression(P<0.01), and down-regulated bcl-2 protein exprssion (P<0.05). Desipramine obviously inhibited the apoptosis induced by 4.25% PDS, decreased bax and p53 proteins expression, increased bcl-2 protein expression(P<0.05). Exogenous C2-ceremide reversed the effect of desipramine(P<0.05). Conclusion The increase of intracellular ceremide may play an important role in the PMCs apoptosis induced by high glucose PDS.

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糖尿病肾病专题

临床研究

基础研究