Efficacy of antisense monocyte chemoattractant protein-1 (MCP-1) in a rat model of mesangial proliferative glomerulonephritis

Abstract

Objective: The effects of inhibition of monocyte chemoattractant protein-1 (MCP-1) on a rat model of mesangial proliferative glomerulonephritis (MsPGN) were evaluated. Methods: The anti-Thy-1 MsPGN model was developed by intravenously injecting anti-Thy-1 monoclonal antibodies into rats, followed by an injection of mesangial cells transfected with antisense MCP-1 into the renal artery. Exogenous cells were detected by in situ hybridization. Rats (40 total) were randomly divided into five groups: SO (sham operation), TG (Thy-1 glomerulonephritis model), MC (non-transfected normal rat mesangial cell), BC (pLXSN empty vector or blank control), and AM (antisense MCP-1 transfection) groups. Effects of exogenous MCP-1 on urinary protein excretion rate, biochemical parameters, and pathological changes were evaluated. Expression of MCP-1 and transforming growth factor-β₁ (TGF-β₁) were detected by immunohistochemistry. mRNA expression of MCP-1, TGF-β₁, and CC chemokine receptor 2 (CCR2) were detected by RT-PCR. Results: Exogenous MCP-1 cDNA was successfully transfected into mesangial cells. Exogenous mesangial cells were detected in glomeruli by in situ hybridization. Glomerular mesangial cell proliferation, 24-h urinary protein excretion rate, mRNA expression of MCP-1, TGF-β₁, and CCR2, and protein expression of MCP-1 all decreased in the AM group as compared to the control group (p?<?0.05), but there was no significant difference in the expression level of TGF-β₁ protein. Conclusions: (1) Mesangial cells can be used as a vector to transfect exogenous genes into kidneys; (2) antisense MCP-1 decreases mesangial cell proliferation and pathological injury in MsPGN model rats by decreasing expression of MCP-1 and CCR2; and (3) antisense MCP-1 suppressed mesangial cell proliferation and matrix accumulation in anti-Thy-1 MsPGN model rats, which did not entirely depend on TGF-β_1.     

Synergistic action of inflammation and lipid dysmetabolism on kidney damage in rats

In kidney disease, inflammation and lipid dysmetabolism are often associated together, however, the effect and mechanism of inflammatory mediators and lipid dysmetabolism on kidney damage is still unclear. In this study, Wistar rats were randomized into four groups: normal diet?+?saline (Group N), high-fat diet (HF)+?saline (Group HF), normal diet?+?adriamycin (Group ADR), HF?+?adriamycin (Group ADR?+?HF). After 10?weeks of feeding, rats in each group were randomly sacrificed. We found that the protein content of urine in ADR and ADR?+?HF groups were significantly higher than that of group N and HF while the serum levels of total protein and albumin in the ADR and ADR?+?HF groups decreased correspondingly. The serum levels of triglyceride, total cholesterol and low-density lipoprotein in the HF, ADR and ADR?+?HF groups increased. In the treatment groups, mesangial proliferation, matrix accumulation, tubular vacuolization, inflammatory cell infiltration and fat deposition were detected. These pathological changes were the most serious in the ADR?+?HF group. The expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) were increased in each treatment group, especially in the ADR?+?HF group. Our results suggested that the inflammatory factors and abnormal lipid levels can activate the inflammatory response in kidney of the Wistar rats, and lead to a series of pathological changes in renal tissue, and inflammatory factors and lipid dysmetabolism can aggravate damage in the kidney.     

肿瘤细胞上清液对成纤维细胞表型转变及血管内皮生长因子-A表达的影响

目的检测肿瘤细胞上清液对成纤维细胞的激活情况及激活后血管内皮生长因子-A(VEGF-A)表达的变化规律。方法 MTT法检测普通培养液、含转化生长因子-β1(TGF-β1)的普通培养液以及肿瘤细胞上清液组成的条件培养液对成纤维细胞生长情况的影响,用RT-PCR、Western blot及免疫组织化学法检测不同培养条件下成纤维细胞的α-平滑肌肌动蛋白(α-SMA)与VEGF-A的表达。结果肿瘤细胞上清液对成纤维细胞的生长有一定的促进作用。含TGF-β1的普通培养液比普通培养液更有利于成纤维细胞转化为肌成纤维细胞,并且能维持肌成纤维细胞的表型,但是二者均不表达VEGF-A;条件培养液能促进成纤维细胞稳定表达α-SMA和VEGF-A,二者在培养后第1天均开始表达,第3天表达量达到峰值,第3天以后表达稳定。结论肿瘤细胞上清液能够有效、稳定地激活成纤维细胞为肌成纤维细胞,成纤维细胞的激活程度影响VEGF-A的表达,二者均具有最佳的激活时间点,并且最佳时间点相一致,最佳激活点的成纤维细胞有望成为一种可用于移植的促进血管重建的细胞。     

血管紧张素1-7对高糖诱导人肾小管上皮细胞转分化的影响及其机制

目的 研究血管紧张素1-7（Ang 1-7）对高糖诱导人肾小管上皮细胞（HK-2）转分化的影响及其可能机制。 方法 培养HK-2细胞分组如下：对照组（N组）、高糖组（H组）、高糖+Ang 1-7组（A组）、高糖+Ang 1-7+A779组（D组）、高糖+吡格列酮组（P组）。Western印迹检测各组HK-2细胞过氧化物酶体增殖物激活受体γ（PPAR-γ）及α平滑肌肌动蛋白（α-SMA）的蛋白表达;实时定量PCR检测HK-2细胞PPAR-γ及α-SMA的mRNA表达;免疫荧光检测α-SMA表达。 结果 Ang 1-7可上调高糖刺激下HK-2细胞PPAR-γ蛋白及mRNA表达（P < 0.05）;抑制高糖刺激的α-SMA蛋白及mRNA表达（P < 0.05）。这种作用与PPAR-γ激动剂吡格列酮类似。给予Mas受体抑制剂A779后,Ang 1-7的上述作用可被部分抑制。 结论 Ang 1-7在体外可通过上调PPAR-γ表达,从而部分抑制高糖诱导的α-SMA表达,实现其抑制转分化的作用,而这种作用部分通过Mas受体所介导。     

转化生长因子β1基因转染兔颞下颌关节滑膜间充质干细胞及其表达

目的 构建TGF-β1基因的重组腺相关病毒载体并将其转入兔颞下颌关节滑膜间充质干细胞(SMSCs)中,对转染后外源性TGF-β1 mRNA和蛋白的表达进行检测.方法 含TGF-β1全长cDNA的质粒pCMV6-XL4和质粒pAAV-MCS用EcoR Ⅰ+Xba Ⅰ进行双酶切后连接,转化大肠杆菌DHSα感受态细胞,获得重组质粒pAAV-MCS-TGF-β1.通过酶切和DNA测序鉴定重组质粒的正确性.采用磷酸钙共沉淀法,以重组质粒pAAV-MCS-TGF-β1和pAAV-RC、pHelper共转染AAV-293细胞,产生具有传染性的病毒颗粒;斑点杂交方法检测重组病毒的滴度,并转染体外培养的SMSCs.以逆转录一聚合酶链反应(RT-PCR)、Western blot分别检测目的 基因及蛋白的表达.结果 成功地构建TGF-β1基因腺相关病毒重组质粒,病毒滴度约为3.6×1013vp/ml,感染的SMSCs能稳定、高效地表达外源性目的 基因及蛋白.结论 重组腺相关病毒载体rAAV-TGF-β1能有效感染SMSCs并表达目的基因.     

末端岩藻糖基化抑制剂对环孢素诱导的肾脏上皮-间充质转化的影响及其机制

目的  探讨末端岩藻糖基化抑制剂2-脱氧-D-半乳糖（2-D-gal）对环孢素（CsA）诱导的肾脏上皮-间充质转化（EMT）的影响及其机制。方法  将15只8~10周的雄性C57BL/6小鼠随机分为对照组（Ctrl组）、CsA组和CsA+2-D-gal组,每组各5只。通过蛋白质印迹法检测Ctrl组和CsA组小鼠肾脏组织岩藻糖基转移酶1（FUT1）和EMT相关蛋白E-cadherin、Vimentin、α-平滑肌肌动蛋白（α-SMA）的表达,免疫荧光法检测Ctrl组和CsA组小鼠肾脏组织末端岩藻糖的表达,Masson染色检测各组小鼠肾脏组织纤维化情况,并检测各组小鼠血尿素氮和血清肌酐水平。体外建立CsA诱导肾小管上皮HK2细胞EMT模型,分别用0、2.5、5.0和10.0 μmol/L的CsA刺激HK2细胞24 h,另将HK2细胞分为Ctrl组、2-D-gal组、CsA组和CsA+2-D-gal组,观察不同浓度CsA刺激后及各组HK2细胞形态,通过蛋白质印迹法检测不同浓度CsA刺激后及各组HK2细胞FUT1、E-cadherin、Vimentin和α-SMA的表达,免疫荧光法检测Ctrl组和CsA组HK2细胞末端岩藻糖的表达。结果  与Ctrl组比较,CsA组小鼠肾脏组织E-cadherin的蛋白相对表达量下降,FUT1、Vimentin和α-SMA蛋白相对表达量均升高（均为P < 0.05）,小鼠肾脏组织末端岩藻糖表达增多。与Ctrl组比较,CsA组和CsA+2-D-gal组小鼠的血尿素氮和血清肌酐水平均升高,与CsA组比较,CsA+2-D-gal组小鼠的血尿素氮和血清肌酐水平均降低（均为P < 0.05）。与Ctrl组比较,CsA组和CsA+2-D-gal组小鼠肾脏组织胶原纤维沉积均增多,α-SMA蛋白相对表达量均升高;与CsA组比较,CsA+2-D-gal组小鼠肾脏组织胶原纤维沉积减少,α-SMA蛋白相对表达量下降（均为P < 0.05）。随着CsA的浓度增加,HK2细胞的形态由正常的鹅卵石样逐渐变长变细,HK2细胞FUT1、Vimentin和α-SMA蛋白相对表达量升高,E-cadherin蛋白相对表达量下降,呈浓度依赖性。与Ctrl组比较,CsA组HK2细胞末端岩藻糖表达增多。CsA处理的基础上联合2-D-gal干预后,CsA+2-D-gal组的HK2细胞形态恢复到与正常HK2细胞形态相似。与CsA组比较,CsA+2-D-gal组的HK2细胞E-cadherin蛋白相对表达量升高,Vimentin和α-SMA蛋白相对表达量均下降（均为P < 0.05）。结论  CsA在体内和体外均可诱导EMT发生,并且伴有末端岩藻糖基化水平增加。2-D-gal可以通过抑制末端岩藻糖基化来抑制CsA诱导的EMT。     

周期性张力对骨髓间充质干细胞分化的血管平滑肌细胞的表型调节

目的 探讨周期性张力对大鼠骨髓间充质干细胞(BMSCs)诱导分化的血管平滑肌细胞(VSMCs)的表型的调节机制.方法 原代全骨髓法培养大鼠BMSCs,流式细胞术鉴定细胞.作成脂、成骨、成平滑肌细胞方向诱导,验证BMSCs的多向分化潜能.将细胞分为4组:A组用含10 μg/L转化生长因子-β1(TGF-β1)的完全培养基培养,B组用幅度10％、频率1 Hz周期性张力诱导,C组采用TGF-β1+周期性张力联合诱导,D组用含10％胎牛血清(FBS)的DMEM/F12培养基培养作对照.3d后观察诱导后的细胞形态,并行反转录-聚合酶链反应(RT-PCR)检测肌动蛋白(α-actin)、平滑肌肌球蛋白重链(SM-MHC)、钙调节蛋白1(calponin1)、钙调节蛋白3(calponin3)的mRNA表达水平,Western blot观察细胞内α-actin、SM-MHC、calponin1、calponin3蛋白表达水平.结果 经流式细胞术鉴定,所培养细胞为BMSCs.诱导3d后,A、B、C3组的VSMC标志物均较D组明显升高,以SM-MHC和calponin3增加为主.A组(0.919 2±0.028 1)较B组(0.823 6±0.024 6)的SM-MHC蛋白表达水平高,但低于C组(1.043 1±0.090 7),其差异均有统计学意义(P＜0.05).C组中calponin3 mRNA表达量比蛋白表达量变化更明显,而calponin1蛋白表达量和mRNA表达量同步增高.结论 周期性张力能够诱导BMSCs分化为VSMCs,对分化的VSMCs的表型调节还需要细胞因子的参与.     

Impact of STAT1-siRNA transfection on the expressions of STAT3 and transforming growth factor β1 in human glomerulur mesangial cells induced by high glucose

Objective To observe the cell proliferation and the protein expression of STAT1,phosphorylation of STAT1 (p-STAT1), STAT3, p-STAT3 and transforming growth factor β1 (TGF-β1) in human glomerulur mesangial cells (HMCs) induced by high glucose after STAT1-siRNA transfection. Methods Three STAT1-siRNA sequences were designed and synthetized. HMCs in 6-well plate were transiently transfected with STAT1-siRNA using Lipofectamine 2000. After transfection for 48 h or 72 h, STAT1 mRNA and protein expression were detected by real-time PCR and Western blotting, respectively, to choose the effective sequence in later experiments. After transfection for 24 h and stimulated with 25 mmol/L glucose for 24 h, 48 h, 72 h, cell proliferation was measured by MTT assays, the protein expressions of STAT1, p-STAT1, STAT3 and p-STAT3 were detected by Western blotting, the expression of TGF-β1 was detected by ELISA in each group. Results High glucose could stimulate HMCs proliferation. The protein expressions of p-STAT1, p-STAT3 and TGF-β1 were increased in the group stimulated by high glucose (P＜0.05). The protein expressions of p-STAT3 and TGF-β1 were further increased in HMCs induced by high glucose after STAT1-siRNA transfection (P＜0.05). Conclusions Under high glucose conditions, JAK-STAT signal transduction pathway of HMCs can be activated, then it is far greater when HMCs are induced by high glucose after STAT1-siRNA transfection. The secretion of TGF-β1 is increased in HMCs under the state of high glucose, and it is further increased after STAT1-siRNA transfection, which is related to the kidney fibrosis.     

Involvement of ERCC1 in the pathogenesis of osteoarthritis through the modulation of apoptosis and cellular senescence

DNA damage is a cause of age related pathologies, including osteoarthritis (OA). Excision repair cross complementation group 1 (ERCC1) is an endonuclease required for DNA damage repair. In this study we investigated the function of ERCC1 in chondrocytes and its association with the pathophysiology of OA. ERCC1 expression in normal and osteoarthritic cartilage was assessed, as were changes in ERCC1 expression in chondrocytes under catabolic stress. Inhibiting ERCC1 in chondrocytes under interleukin‐1β stimulation using small interfering RNA (siRNA) was also evaluated. Finally, cellular senescence and apoptosis were examined in relation to ERCC1 function. ERCC1 expression was decreased in OA cartilage and increased within 4 h of exposure to interleukin (IL)‐1β, but decreased after 12 h. The inhibition of ERCC1 by siRNA increased the expression of matrix metallopeptidase 13 and decreased collagen type II. ERCC1 inhibition also increased the number of apoptotic and senescent cells. The inhibition of ERCC1 in chondrocytes increased their expression of OA related proteins, apoptosis, cellular senescence, and hypertrophic‐like changes which suggest that ERCC1 is critical for protecting human chondrocytes (HCs) from catabolic stresses and provides insights into the pathophysiology of OA and a potential target for its treatment. (191) © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1326–1332, 2014.     

前列腺癌患者外周血中CD4^＋CD25^high调节性T细胞及调节因子TGF-β1和COX-2的表达

目的：通过检测前列腺癌患者以及健康志愿者外周血中CD4＋CD25high调节性T细胞、TGF-β1及COX-2的表达,初步探讨CD4＋CD25high调节性T细胞在前列腺癌发病机制中的作用及其与TGF-β1和COX-2的相关性。方法：应用流式细胞术检测30例前列腺癌患者治疗前后（其中前列腺癌局限组11例,非局限组19例）及20例健康志愿者外周血单个核细胞（PBMC）中CD4＋CD25high调节性T细胞占CD4＋T细胞的比例;应用酶联免疫吸附试验（ELISA）检测其外周血清中TGF-β1和COX-2的表达。对前列腺癌患者上述指标进行术前术后对比分析,另对CD4＋CD25high调节性T细胞与TGF-β1及COX-2的相关性进行分析;并探讨上述指标在前列腺癌患者局限组和非局限组间是否存在差异性。结果：流式细胞术检测显示,前列腺癌患者治疗前PBMC中CD4＋CD25high调节性T细胞占CD4＋T细胞的比例为（18.32±7.49）%,高于健康志愿者对照组（7.77±1.86）%（P〈0.05）。前列腺癌患者治疗后其比值为（17.34±5.87）%,较治疗前稍减低,但两者相比无显著差异（P〉0.05）。ELISA检测外周血清中TGF-β1和COX-2显示,前列腺癌组分别为（215.97±55.16）ng/ml和（6.88±5.14）ng/ml,对照组分别为（149.75±47.11）ng/ml和（5.65±2.69）ng/ml;前列腺癌患者外周血清中TGF-β1的表达水平高于健康志愿者对照组（P〈0.05）,COX-2的表达水平与对照组无显著差异（P〉0.05）。通过多重线性回归分析表明,前列腺癌患者PBMC中CD4＋CD25high调节性T细胞的表达与血清中TGF-β1和COX-2的表达无显著相关。前列腺癌局限组和非局限组外周血中CD4＋CD25high调节性T细胞、TGF-β1及COX-2的表达均无显著性差异（P〉0.05）。结论：前列腺癌患者PBMC中CD4＋CD25high调节性T细胞可能参与前列腺癌的发生,其增殖机制与血清中TGF-β1和COX-2的表达无关,可能与肿瘤本身及肿瘤局部微环境相关。     

HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation

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Differential role of natural killer group 2D in recognition and cytotoxicity of hepatocyte‐like cells derived from embryonic stem cells and induced pluripotent stem cells

Stem cell–based approaches have the potential to address the organ shortage in transplantation. Whereas both embryonic stem cells and induced pluripotent stem cells have been utilized as cellular sources for differentiation and lineage specification, their relative ability to be recognized by immune effector cells is unclear. We determined the expression of immune recognition molecules on hepatocyte‐like cells (HLC) generated from murine embryonic stem cells and induced pluripotent stem cells, compared to adult hepatocytes, and we evaluated the impact on recognition by natural killer (NK) cells. We report that HLC lack MHC class I expression, and that embryonic stem cell–derived HLC have higher expression of the NK cell activating ligands Rae1, H60, and Mult1 than induced pluripotent stem cell–derived HLC and adult hepatocytes. Moreover, the lack of MHC class I renders embryonic stem cell–derived HLC, and induced pluripotent stem cell–derived HLC, susceptible to killing by syngeneic and allogeneic NK cells. Both embryonic stem cell–derived HLC, and induced pluripotent stem cell–derived HLC, are killed by NK cells at higher levels than adult hepatocytes. Finally, we demonstrate that the NK cell activation receptor, NKG2D, plays a key role in NK cell cytotoxicity of embryonic stem cell–derived HLC, but not induced pluripotent stem cell–derived HLC.     

Effects of triptolide on proliferation and apoptosis in rat mesangial cells induced by transforming growth factor β1 and related mechanisms

Objective To investigate the effects of triptolide on proliferation, apoptosis and the changes of Ski, Smad3, Smad7 and collagen type Ι (ColΙ) in cultured rat mesangial cells induced by transforming growth factor (TGF)?β1. Methods Cultured HBZY?1 rat mesangial cells were divided into 5 groups: (1)normal control group; (2)TGF?β1 group (10 μg/L); (3)-(5)triptolide (0.4, 2, 10 μg/L)+TGF?β1 (10 μg/L) groups. The cell proliferation was detected by MTT. Apoptosis of mesangial cells was detected by TUNEL assay. The expressions of Ski, Smad3, Smad7 mRNA were examined by real?time quantitative PCR. The expressions of Ski, Smad3, Smad7 and ColΙ protein were detected by Western blotting. The localizations of Ski and Smad3 protein were detected by laser confocal fluorescence microscope. Results Compared with the normal control, TGF?β1 (10 μg/L) significantly stimulated mesangial cells proliferation, while decreased apoptosis. The mRNA and protein expressions of Ski, Smad7, Smad3 and ColΙ protein expression in TGF?β1 group were increased (P＞0.05). In comparison with TGF?β1 group, triptolide could significantly inhibit TGF?β1?induced mesangial cells proliferation in dose?dependent manner, and promote the apoptosis of mesangial cells. In TGF?β1 group, mRNA and protein expresscons of Ski and Smad7 were increased (P<0.05), Smad3 mRNA and protein were decreased (P＞0.05), and ColΙ protein was decreased (P<0.01). In comparison with TGF?β1 group, fluorescence intensity of Ski, Smad3 proteins was significantly increased in cytoplasm, while decreased in nucleus. Conclusions Triptolide can inhibit TGF?β1?induced mesangial cells proliferation through regulating the expressions of Ski, Smad7 mRNA and protein, inhibiting Ski. Smad7 translocation to the nucleus, and down?regulating Smad3 mRNA and protein expression. Triptolide can promote apoptosis of mesangial cells.     

Effects of silibinin on expression of integrin linked kinase,transforming growth factor β1 and α-smooth muscle actin in rat peritoneal mesothelial cells induced by high glucose

Objective To observe the effect of silibinin on the expression of integrin linked kinase (ILK), transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in rat peritoneal mesothelial cells (RPMCs) induced by high glucose. Methods RPMCs were isolated, cultured and passaged by trypsin, then identified. The second generation of cultured RPMCs were used in the experiment. RPMCs were divided into normal control group, high glucose(1.5%, 2.5%, 4.25%) for 24 hours, high glucose (2.5%) for 12, 24, 48, 72 hours, high glucose (2.5%) for 24 hours after silibinin (5, 10, 20 mg/L) preincubate for 2 hours. ILK and α-SMA mRNA were detected by real-time PCR. ILK protein was detected by Western blotting. TGF-β1 protein in supernatants was detected by ELISA. Results Compared with the control group, the expresssion of ILK, TGF-β1 and α-SAM was significantly increased in groups stimulated by high glucose (all P＜0.05). Silibinin could significantly decrease the expression of ILK, TGF-β1 and α-SMA induced by high glucose (all P＜0.05). Conclusions High glucose can up-regulate the expression of ILK, TGF-β1 and α-SMA. Silibinin can reverse these changes.     

NOD小鼠未成熟树突状细胞体外诱导淋巴细胞生成并扩增调节性T细胞的研究

目的 探索非肥胖糖尿病(non-obese diabetic,NOD)小鼠未成熟树突状细胞(immature dendritic cell,imDC)诱导并扩增调节性T细胞(regulatory T cells,Treg)的优化方案.方法 分离、培养NOD小鼠骨髓来源的imDC和淋巴细胞,并进行混合淋巴细胞培养,分别加...     

Fibroblast growth factor-2 increases the renal recruitment and attachment of HIV-infected mononuclear cells to renal tubular epithelial cells

The role of circulating growth factors in the pathogenesis of childhood HIV-1-associated nephropathy (HIVAN) is not clearly understood. In previous studies, we found a significant accumulation of fibroblast growth factor-2 (FGF-2) in the circulation and kidneys of children with HIVAN. The purpose of this study was to determine whether circulating FGF-2 may play a role in the pathogenesis of HIVAN by increasing the renal recruitment and attachment of HIV-infected mononuclear cells to renal epithelial cells. Using in vitro cell adhesion assays, we showed that FGF-2 increased the attachment of peripheral blood mononuclear cells (PBMCs) to fibronectin-coated tissue culture dishes by approximately threefold through a mechanism that involved the 5 integrin subunit. In addition, we found that FGF-2 induces a similar increase in the attachment of HIV-infected PBMCs and monocytes/macrophages to plastic tissue culture dishes and to monolayers of primary renal tubular epithelial cells harvested from the urine of HIV-infected children with renal disease. Finally, we injected 16 adult C57Bl6/J male mice with recombinant adenoviral vectors carrying either the LacZ gene or a secreted form of human FGF-2 (5×10⁸ pfu/mouse) and demonstrated that high levels of circulating FGF-2 can increase the renal recruitment of circulating inflammatory cells and induce transient tubulointerstitial injury in vivo. These data suggest that FGF-2 may have an immunomodulatory role in the pathogenesis of HIVAN by recruiting HIV-infected cells in the kidney.