Soluble Urokinase Receptor Levels Are Correlated with Focal Segmental Glomerulosclerosis Lesions in IgA Nephropathy: A Cohort Study from China

Background

Soluble urokinase receptor (suPAR) may be involved in the pathological mechanisms of focal segmental glomerulosclerosis (FSGS) changes. However, it remains unclear whether suPAR is correlated with the FSGS-like lesions in IgA nephropathy (IgAN).

Methods

We measured the plasma suPAR levels in 138 patients with IgAN, and then their clinical and pathological relationships were analyzed.

Results

We found that the plasma suPAR levels were significantly correlated with age and renal function by both univariate and multivariate analysis in our IgAN patient cohort. Female had higher plasma suPAR levels and no significant correlation was observed between plasma suPAR levels and 24-h urine protein and highly sensitive C-reaction protein with multivariate analysis. In our cohort, sixty of these IgAN patients could be diagnosed with a type of FSGS lesions. The plasma suPAR levels were higher in the IgAN patients with FSGS lesions than in the IgAN patients without FSGS lesions by univariate (P < 0.0001) and multivariate (P < 0.001) analysis adjusting for other predictor variables, which might be helpful to differentiate the pathological changes with and without FSGS lesions. And the optimal cutoff value was 1806 pg/ml in this study. The plasma suPAR concentrations were also associated with the degree of tubular atrophy/interstitial fibrosis in both univariate and multivariate analysis. In multivariate analysis, the plasma suPAR levels were correlated with the percentage of crescents, not global sclerosis and arterial lesions.

Conclusions

Our study suggested that the plasma suPAR levels were associated with age, gender, renal function, the degree of tubular atrophy/interstitial fibrosis and the percentage of crescent formation. The plasma suPAR might be a potential predictor for the presence of FSGS pathological lesions in Chinese patients with IgAN.     

DNA Methylation in Cosmc Promoter Region and Aberrantly Glycosylated IgA1 Associated with Pediatric IgA Nephropathy

IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. Elevation of aberrantly glycosylated IgA1 is a key feature of it. The expression of the specific molecular chaperone of core1ß1, 3galactosyl transferase (Cosmc) is known to be reduced in IgAN. We aimed to investigate whether the methylation of CpG islands of Cosmc gene promoter region could act as a possible mechanism responsible for down-regulation of Cosmc and related higher secretion of aberrantly glycosylated IgA1in lymphocytes from children with IgA nephropathy. Three groups were included: IgAN children (n = 26), other renal diseases (n = 11) and healthy children (n = 13). B-lymphocytes were isolated and cultured, treated or not with IL-4 or 5-Aza-2’-deoxycytidine (AZA). The levels of DNA methylation of Cosmc promotor region were not significantly different between the lymphocytes of the three children populations (P = 0.113), but there were significant differences between IgAN lymphocytes and lymphocytes of the other two children populations after IL-4 (P<0.0001) or AZA (P<0.0001). Cosmc mRNA expression was low in IgAN lymphocytes compared to the other two groups (P<0.0001). The level of aberrantly glycosylated IgA1 was markedly higher in IgAN group compared to the other groups (P<0.0001). After treatment with IL-4, the levels of Cosmc DNA methylation and aberrantly glycosylated IgA1 in IgAN lymphocytes were remarkably higher than the other two groups (P<0.0001) with more markedly decreased Cosmc mRNA content (P<0.0001). After treatment with AZA, the levels in IgAN lymphocytes were decreased, but was still remarkably higher than the other two groups (P<0.0001), while Cosmc mRNA content in IgAN lymphocytes were more markedly increased than the other two groups (P<0.0001). The alteration of DNA methylation by IL-4 or AZA specifically correlates in IgAN lymphocytes with alterations in Cosmc mRNA expression and with the level of aberrantly glycosylated IgA1 (r = −0.948, r = 0. 707). Our results suggested that hypermethylation of Cosmc promoter region could be a key mechanism for the reduction of Cosmc mRNA expression in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.     

可溶性VEGF受体Flt-1的基因克隆及其活性产物在原核中的表达

可溶性血管内皮细胞生长因子受体 ( Flt- 1 )具有受体拮抗剂作用 ,可竞争结合血管内皮细胞生长因子 ,( VEGF)并与其膜表面受体 Flt- 1及 KDR形成异源二聚体 ,最终阻断 VEGF的生物学活性 .利用 RT- PCR技术从人脐静脉内皮细胞扩增出 Flt- 1胞外 ～ 区 c DNA片段 ,通过基因重组将该片段克隆于谷胱甘肽转移酶 ( GST)融合蛋白表达载体 PGEX2 -T中 ,连接产物转化大肠杆菌XL1 - blue,经 IPTG诱导可获大量稳定表达的 Flt- 1 - GST融合蛋白 .该表达产物经变性复性处理后 ,可特异性结合 12 5 - VEGF.大量具有活性的可溶性 Flt- 1的获得有助于新的抗肿瘤血管形成方法的探索 .     

Role of Endothelial Soluble Epoxide Hydrolase in Cerebrovascular Function and Ischemic Injury

Soluble Epoxide Hydrolase (sEH) is a key enzyme in the metabolism and termination of action of epoxyeicosatrienoic acids, derivatives of arachidonic acid, which are protective against ischemic stroke. Mice lacking sEH globally are protected from injury following stroke; however, little is known about the role of endothelial sEH in brain ischemia. We generated transgenic mice with endothelial-specific expression of human sEH (Tie2-hsEH), and assessed the effect of transgenic overexpression of endothelial sEH on endothelium-dependent vascular reactivity and ischemic injury following middle cerebral artery occlusion (MCAO). Compared to wild-type, male Tie2-hsEH mice exhibited impaired vasodilation in response to stimulation with 1 µM acetylcholine as assessed by laser-Doppler perfusion monitoring in an in-vivo cranial window preparation. No difference in infarct size was observed between wild-type and Tie2-hsEH male mice. In females, however, Tie2-hsEH mice sustained larger infarcts in striatum, but not cortex, compared to wild-type mice. Sex difference in ischemic injury was maintained in the cortex of Tie2-hsEH mice. In the striatum, expression of Tie2-hsEH resulted in a sex difference, with larger infarct in females than males. These findings demonstrate that transgenic expression of sEH in endothelium results in impaired endothelium-dependent vasodilation in the cerebral circulation, and that females are more susceptible to enhanced ischemic damage as a result of increased endothelial sEH than males, especially in end-arteriolar striatal region.     

Glomerular Endothelial Cell Injury and Focal Segmental Glomerulosclerosis Lesion in Idiopathic Membranous Nephropathy

Background

Focal segmental glomerulosclerosis (FSGS) lesions have often been discussed as a negative predictor in idopathic membranous nephropathy (MN). The mechanism of the development of FSGS lesion in MN is still uncertain.

Methods

From 250 cases of MN, 26 cases contained FSGS lesion. We compared the clinicopathological characteristics between MN cases with FSGS lesion [MN-FSGS(+)] and MN without FSGS lesion [MN-FSGS(−)], matched for gender, age, stage of MN.

Results

The glomerular filtration rate (eGFR) was significantly lower in MN-FSGS(+) cases compared to MN-FSGS(−), although nephrotic syndrome, hematuria, and systolic blood pressure levels were not significantly different between the two groups. Pathologically, glomeruli in MN-FSGS(+) cases showed narrowing and loss of glomerular capillaries with separating from GBM or disappearance of CD34+ endothelial cells, and accumulation of extracellular matrix (ECM) in capillary walls, indicating the development of glomerular capillary injury. These findings of endothelial injury were seen even in MN-FSGS(−) cases, but they were more prominent in MN-FSGS(+) than MN-FSGS(−) by computer assessed morphometric analysis. In MN-FSGS(+) cases, 44 out of 534 glomeruli (8.2%) contained FSGS lesions (n = 31, NOS lesion; n = 13, perihilar lesion). Significant thickness of GBM with ECM accumulation was evident in MN-FSGS(+) cases. Podocyte injury with effacement of foot processes was also noted, but the expression of VEGF on podocytes was not different between the two groups, which suggests that the significant thickness of capillary walls may influence the function of VEGF from podocyte resulting in the glomerular capillary injury that contribute to the development of FSGS lesion in MN.

Conclusion

Glomerular capillary injury was seen in all MN cases. Furthermore, the prominent injuries of glomerular capillaries may be associated with the deterioration of eGFR and the formation of FSGS lesions in MN.     

Glomerular Endothelial Cell Injury and Damage Precedes That of Podocytes in Adriamycin-Induced Nephropathy

The role of podocytes in the development and progression of glomerular disease has been extensively investigated in the past decade. However, the importance of glomerular endothelial cells in the pathogenesis of proteinuria and glomerulosclerosis has been largely ignored. Recent studies have demonstrated that endothelial nitric oxide synthatase (eNOS) deficiency exacerbates renal injury in anti-GBM and remnant kidney models and accelerates diabetic kidney damage. Increasing evidence also demonstrates the importance of the glomerular endothelium in preventing proteinuria. We hypothesize that endothelial dysfunction can initiate and promote the development and progression of glomerulopathy. Administration of adriamycin (ADR) to C57BL/6 mice, normally an ADR resistant strain, with an eNOS deficiency induced overt proteinuria, severe glomerulosclerosis, interstitial fibrosis and inflammation. We also examined glomerular endothelial cell and podocyte injury in ADR-induced nephropathy in Balb/c mice, an ADR susceptible strain, by immunostaining, TUNEL and Western blotting. Interestingly, down-regulation of eNOS and the appearance of apoptotic glomerular endothelial cells occurred as early as 24 hours after ADR injection, whilst synaptopodin, a functional podocyte marker, was reduced 7 days after ADR injection and coincided with a significant increase in the number of apoptotic podocytes. Furthermore, conditioned media from mouse microvascular endothelial cells over-expressing GFP-eNOS protected podocytes from TNF-α-induced loss of synaptopodin. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADR-induced nephropathy. Glomerular endothelial cells may protect podocytes from inflammatory insult. Understanding the role of glomerular endothelial dysfunction in the development of kidney disease will facilitate in the design of novel strategies to treat kidney disease.     

小鼠天然可溶性VEGF受体基因sflt-1的克隆及鉴定

 可溶性血管内皮细胞生长因子受体 (sFlt 1 )与膜表面受体Flt 1竞争结合血管内皮细胞生长因子 (VEGF) ,并且与膜表面受体Flt 1及KDR形成异源二聚体 .完全阻断VEGF的生物学活性 ,除与sFlt 1的结合部位结构域有关外 ,还与整个蛋白质分子的高效分泌表达有关 .而蛋白质分子的高效分泌表达与蛋白质在细胞内高尔基体及内质网的加工密切相关 ,基因工程重组可溶性受体由于一些尚未明了的原因 ,往往不能高效表达 ,从而大大影响了其应用价值 .利用RT PCR技术从胚胎小鼠中扩增出天然可溶性VEGF受体基因sflt 1 ,克隆于pcDNA3载体中 ,在COS 7细胞中短暂表达 ;并克隆至pET42b载体中 ,经IPTG诱导后 ,可大量稳定表达与His Tag形成的融合蛋白 ,经HisNi柱纯化 ,可特异性结合VEGF .可溶性受体sFlt 1在肿瘤组织的高效表达可有效阻断新生血管的形成 ,从而为肿瘤的治疗探索一种方法 .     

紫癜性肾炎患儿血清Gd-IgA1、sFlt-1、IgA/C3比值与肾损伤和疗效的关系研究

摘要 目的：探讨紫癜性肾炎（HSPN）患儿血清半乳糖缺陷免疫球蛋白A1（Gd-IgA1）、可溶性fms-样酪氨酸激酶受体l（sFlt-1）、免疫球蛋白A（IgA）/补体C3（C3）比值与肾损伤和疗效的关系。方法：选取成都大学附属医院2019年12月至2021年12月确诊为HSPN的151例患儿作为病例组。另选取同期体检健康的志愿儿童100例作为对照组。对比两组血清Gd-IgA1、sFlt-1、IgA/C3比值、肾功能指标[尿素氮（BUN）、血肌酐（Scr）、24 h尿蛋白（UP）定量（24hUPE）和UP/Scr]。采用Pearson法分析血清Gd-IgA1、sFlt-1、IgA/C3比值与肾功能指标的相关性。对比不同肾脏病理分级和不同疗效患儿的血清Gd-IgA1、sFlt-1、IgA/C3比值。结果：病例组的Gd-IgA1、sFlt-1、IgA/C3比值、BUN、Scr、24hUPE、UP/Scr均高于对照组（P<0.05）。Pearson相关性分析结果显示：Gd-IgA1、sFlt-1、IgA/C3比值与BUN、Scr、24hUPE、UP/Scr均呈正相关（P<0.05）。随着肾脏病理分级的升高,HSPN患儿的血清Gd-IgA1、sFlt-1、IgA/C3比值不断升高（P<0.05）。无效组的Gd-IgA1、sFlt-1、IgA/C3比值高于有效组（P<0.05）。结论：Gd-IgA1、sFlt-1、IgA/C3比值升高参与了HSPN患儿的疾病进展,可导致肾损伤,加重肾脏病理改变,临床可根据上述指标变化指导治疗。     

Rat Macrophages in Experimental IgA Nephropathy

To test whether the peripheral macrophage functions as an early index of oxygen free radical release in association with the development of IgA nephropathy (IgAN), we studied female Lewis rats. IgAN was produced by treatment over 8 weeks with 0.1% bovine gamma globulin (BGG) in drinking water, followed by three daily intravenous injections of BGG, 1 mg/dose. Fifteen rats were divided randomly into three groups: control, IgAN, and IgAN fed vitamin E 100 IU/kg chow. At the end of the treatment period, rats were placed in individual metabolic cages for 24-h urine collections and then anesthetized with Inactin (100 mg/kg BW) for aspiration of peritoneal macrophages. The results (means ± SD) extended our previous data in male rats, confirming that the elevated proteinuria of IgAN (3.62 ± 0.79 mg/day) was significantly reduced with vitamin E treatment (2.59 ± 0.28 mg/day) in female rats (P< 0.002) More importantly, we indicated for the first time that oxygen free radicals' production by peritoneal macrophages in IgAN was significantly reduced by vitamin E: 1.58 ± 0.91 nmol/10⁶cells/15 min in the untreated group vs 3.28 ± 0.54 nmol/10⁶cells/15 min in the vitamin E-treated group (P< 0.05).     

Uncoupling of Glomerular IgA Deposition and Disease Progression in Alymphoplasia Mice with IgA Nephropathy

Previous clinical and experimental studies have indicated that cells responsible for IgA nephropathy (IgAN), at least in part, are localized in bone marrow (BM). Indeed, we have demonstrated that murine IgAN can be experimentally reconstituted by bone marrow transplantation (BMT) from IgAN prone mice in not only normal mice, but also in alymphoplasia mice (aly/aly) independent of IgA⁺ cells homing to mucosa or secondary lymphoid tissues. The objective of the present study was to further assess whether secondary lymph nodes (LN) contribute to the progression of this disease. BM cells from the several lines of IgAN prone mice were transplanted into aly/aly and wild-type mice (B6). Although the transplanted aly/aly showed the same degree of mesangial IgA and IgG deposition and the same serum elevation levels of IgA and IgA-IgG immune-complexes (IC) as B6, even in extent, the progression of glomerular injury was observed only in B6. This uncoupling in aly/aly was associated with a lack of CD4⁺ T cells and macrophage infiltration, although phlogogenic capacity to nephritogenic IC of renal resident cells was identical between both recipients. It is suggested that secondary LN may be required for the full progression of IgAN after nephritogenic IgA and IgA/IgG IC deposition.     

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.     

Significance of Urinary Full-Length Megalin in Patients with IgA Nephropathy

Background and Objectives

Megalin is highly expressed at the apical membranes of proximal tubular epithelial cells. A urinary full-length megalin (C-megalin) assay is linked to the severity of diabetic nephropathy in type 2 diabetes. This study examined the relationship between levels of urinary C-megalin and histological findings in adult patients with IgA nephropathy (IgAN).

Design, Setting, Participants, & Measurements

Urine samples voided in the morning on the day of renal biopsy were obtained from 73 patients with IgAN (29 men and 44 women; mean age, 33 years) and 5 patients with membranous nephropathy (MN). Renal pathologic variables were analyzed using the Oxford classification of IgAN, the Shigematsu classification and the Clinical Guidelines of IgAN in Japan. The levels of urinary C-megalin were measured by sandwich ELISA.

Results

Histological analysis based on the Oxford classification revealed that the levels of urinary C-megalin were correlated with mesangial hypercellularity in IgAN patients (OR = 1.76, 95% CI: 1.04–3.27, P<0.05). There was a significant correlation between the levels of urinary C-megalin and the severity of chronic extracapillary abnormalities according to the Shigematsu classification in IgAN patients (β = 0.33, P = 0.008). The levels of urinary C-megalin were significantly higher in all risk levels of IgAN patients requiring dialysis using the Clinical Guidelines of IgAN in Japan than in the control group. The levels of urinary C-megalin were significantly higher in the high risk and very high risk grades than in the low risk grade (P<0.05). The levels of urinary C-megalin were significantly higher in MN patients compared to the control group.

Conclusions

The levels of urinary C-megalin are associated with histological abnormalities in adult IgAN patients. There is a possibility that urinary C-megalin is an independent predictor of disease progression of IgAN. In addition, our results suggest that urinary C-megalin is a marker of glomerular abnormalities in various glomerular diseases as well as IgAN.     

Optimal Proteinuria Target for Renoprotection in Patients with IgA Nephropathy

Background

Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.

Methods

We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.

Results

During a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m²/year, P = 0.03).

Conclusion

In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.     

血清降钙素原、可溶性血管内皮生长因子受体1及sofa评分与重症感染的相关性及预后预测价值

摘要 目的：探讨血清降钙素原（PCT）、可溶性血管内皮生长因子受体1（sFIt-1）及序贯器官衰竭（sofa）评分与重症感染的相关性及预后预测价值。方法：选取我院2020年1月到2022年12月收治的60例重症感染患者作为研究对象,依照感染严重程度分为脓毒症组（n=25）,重度脓毒症组（n=20）与脓毒症休克组（n=15）,另选取同期来我院体检的30名健康者作为对照组。对比四组受检者PCT、sFIt-1、sofa评分水平,分析PCT、sFIt-1、sofa与重症感染的相关性。通过对60例重症感染患者的治疗结果情况分为存活组（n=36）和死亡组（n=24）,对比两组患者临床一般情况和PCT、sFIt-1、sofa评分水平,并应用;logistic回归分析分析三者对重症感染的预后预测价值。结果：四组受检者PCT、sFIt-1、sofa评分水平对比差异显著,脓毒症休克组高于重度脓毒症组、脓毒症组和对照组（P＜0.05）;Spearman相关分析结果显示：PCT、sFIt-1、sofa评分与重症感染呈正相关（P＜0.05）;存活组与死亡组患者性别、年龄、感染部位、合并冠心病、糖尿病、高血压基础疾病、病原学、重症监护室（Intensive Care Unit,ICU）住院时间对比无差异（P＞0.05）,存活组与死亡组患者合并心功能不全、急性生理与慢性健康评分（APACHEⅡ）评分、PCT、sFIt-1、sofa评分对比差异显著（P＜0.05）;logistic回归分析结果表明：PCT、sFIt-1、sofa评分为重度感染预后的独立预测指标（P＜0.05）。结论：PCT、sFIt-1、sofa与重症感染呈正相关,且三者水平越高患者死亡率可能越高,因此需针对PCT、sFIt-1、sofa升高的感染患者改良治疗措施,预防预后不良情况。     

Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling

Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R). The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication.     

Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria

There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.     

孢素联合糖皮质激素对IgA肾病患者IgA、C3及IgA/C3影响研究

目的:探讨孢素联合糖皮质激素对IgA肾病患者IgA、C3及IgA/C3的影响。方法:我院收治的IgA肾病住院患者90例,按用药不同分为对照组与实验组。对照组予以醋酸泼尼松片口服,实验组在对照组基础上予以予环孢素软胶囊口服,治疗结束后对患者的血肌酐、血尿酸、24 h尿蛋白定量及IgA、C3、IgA/C3进行检测。结果:与对照组相比,实验组24 h尿蛋白定量水平较低,P0.05;IgA水平及IgA/C3水平较低,P0.05,差异具有统计学意义;两组患者的C3、血肌酐、血尿酸水平无显著差异,无统计学意义(P0.05)。结论:孢素联合糖皮质激素能够显著降低Ig A肾病患者Ig A水平及IgA/C3,对C3水平无影响,对临床有指导意义。     

Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants

The role of adenosine in the regulation of cardiovascular function has long been acknowledged, but only recently has its importance in angiogenesis been appreciated, most notably, through its direct regulation of the proangiogenic growth factor, VEGF. Recent work has established that proangiogenic and antiangiogenic factors, specifically VEGF and and the soluble VEGF receptor fms-like tyrosine kinase-1 (sFlt-1), are directly influenced by hypoxia in placental ischemia. While adenosine has been reported to be an important regulator of VEGF in vascular tissue, the importance of adenosine in regulating VEGF and sFlt-1 in placental tissue is unclear. Here, we have investigated the role of adenosine in the secretion of VEGF and the antiangiogenic protein sFlt-1 in placental villous explants. Under normoxic conditions (6% oxygen), the nonspecific adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT) had no effect on either VEGF (P = 0.38) or sFlt-1 (P = 0.56) secretion. However, under hypoxic conditions (1% oxygen), 8-SPT attenuated the increase in the secretion of both VEGF and sFlt-1 (P < 0.05 and P < 0.005, respectively). Exogenous and the adenosine transporter inhibitor dipyridamole (which increases extracellular levels of adenosine) showed differential effects under normoxic conditions: sFlt-1 levels in media increased significantly (P < 0.05), whereas VEGF was unaffected (P = 0.67 and P = 0.19, respectively). These data indicate that extracellular adenosine can regulate VEGF and sFlt-1 secretion in the hypoxic placenta and could, therefore, control the balance of these competing angiogenic factors in diseases characterized by placental ischemia.