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目的探讨肾清饮抑制肾间质纤维化的可能机制。方法采用腺嘌呤灌胃法建立大鼠肾间质纤维化动物模型,并给予肾清饮和盐酸苯那普利干预治疗,作肾脏病理学检查,并以免疫组化和RT-PCR方法分别检测大鼠肾脏转化生长因子β1（TGF-β1）、金属蛋白酶组织抑制物-1（TIMP-1）的表达。结果各肾清饮干预组肾组织肾间质纤维化程度轻于模型对照组,免疫组化和RT-PCR检测的肾脏TGF-β1、TIMP-1的表达量均少于模型对照组（P〈0.05）。结论肾清饮可通过减少肾组织TGF-β1、TIMP-1的表达,抑制肾间质纤维化的进展。

目的观察氧化苦参碱对慢性肾脏病（CKD）患者血清转化生长因子-β1（TGF-β1）、Ⅲ型胶原（ColⅢ）的影响，探讨其在肾间质纤维化发生发展过程中的作用和治疗价值。方法选取健康对照者10例、慢性肾脏病患者40例，根据肾小球滤过率（GFR）分为轻度肾损害组（GFR〈90mL／min·1．73m^2，CKDI）、中重度肾损害组（GFR〈60mL／min·1．73m^2，CKDⅡ），再分层随机抽样，分为常规治疗组和氧化苦参碱组。利用双抗体夹心酶联免疫吸附法分别检测各研究对象治疗前、后血清TGF-β1、ColⅢ含量，采用t检验比较两组TGF-β1、ColⅢ水平的差异。站果氧化苦参碱组TGF-β1、ColⅢ含量显著低于常规治疗组（P〈0．05）。站论氧化苦参碱可能通过下调TGF-β1、ColⅢ水平，减少ECM沉积，从而达到防止肾间质纤维化的作用。

目的观察氧化苦参碱对慢性肾脏病（CKD）患者血清基质金属蛋白酶-9（MMP-9）、基质金属蛋白酶组织抑制因子-1（TIMP-1）的影响,探讨其在肾间质纤维化发生发展过程中的作用和治疗价值。方法选取健康对照者10例、慢性肾脏病患者40例,根据肾小球滤过率（GFR）分为轻度肾损害组（GFR〈90 mL/min.1.73 m2,CKDⅠ）和中、重度肾损害组（GFR〈60 mL/min.1.73 m2,CKDⅡ）,再分层随机抽样,分为常规治疗组和氧化苦参碱组。利用双抗体夹心酶联免疫吸附法分别检测各组治疗前后血清MMP-9和TIMP-1含量,采用t检验比较两组MMP-9和TIMP-1水平的差异。结果经氧化苦参碱干预后,TIMP-1水平显著低于常规治疗组,而MMP-9水平则显著高于常规治疗组（P〈0.05）。结论氧化苦参碱可下调TIMP-1水平,恢复MMP-9水平,保持MMP-9/TIMP-1平衡,减少细胞外基质（ECM）沉积,防止肾间质纤维化。

Aim： SM934 is a novel water-soluble artemisinin derivative with immunoregulatory activities that has been used to treat murine lupus nephritis. In the current study, we investigated the effects of SM934 on rat experimental membranous nephropathy. Methods： Passive Heymann nephritis （PHN） was induced in SD rats by intraperitoneal injection of anti-FxlA serum. The rats were orally administered SM934 （12.5 and 25 mg.kg-1.d-1） or prednisolone （5 mg.kg-1.d-1） for 28 d. Blood and urine sample, and kidney tissue were collected for analyses. Human complement C3a-induced injury of HK-2 cells was used for in vitro experiments. Results： Treatment of PHN rats with SM934 or prednisolone attenuated the progression of glomerulonephritis and renal fibrosis, as evidenced by the reduced level of proteinuria and circulating antibodies, as well as by the reduced immune complex deposition, reversed podocyte injuries, and attenuated tubulointerstitial fibrosis in the kidneys. Furthermore, the two drugs suppressed TGF- β1 expression and Smad2/3 phosphorylation, and increased Smad7 expression in the kidneys. The two doses of SM934 produced almost identical therapeutic effects on PHN rats. Pretreatment with SM934 or a C3a receptor antagonist blocked the C3a-induced epithelial-mesenchymal transition in HK-2 cells in vitro. Conclusion： SM934 ameliorates kidney injury and attenuates the tubulointerstitial fibrosis in PHN rats by down-regulation of the TGF- β1/Smad signaling pathway.

Aim： To explore the relationship between the signal transducer and activator of transcription 3 （STAT3） signaling and renal fibrosis Methods： Rat renal tubular epithelial NRK-52E cells were treated with angiotensin Ⅱ （Ang Ⅱ）, nicotinamide （an inhibitor of NAD＋- dependent class ⅡI protein deacetylases, SIRT1-7）, or resveratro obstruction （UUO） were used for in vivo studies. Renal interstitial STAT3 acetylation and phosphorylation, fibronectin, collagen I, co （an activator of SIRT1）. Mice underwent unilateral uretera fibrosis was observed with HE and Masson＇s trichrome staining. lagen Ⅳ, and α-smooth muscle actin （α-SMA） levels were examined using Western blotting. Results： Nicotinamide （0.625-10 mmol/L） dose-dependently increased STAT3 acetylation on Lys685 and phosphorylation on Tyr705 in NRK-52E cells, accompanied by accumulation of fibronectin and collagen Ⅳ. Ang Ⅱ increased STAT3 phosphorylation on Tyr705 and the expression of fibronectin, collagen Ⅳ and α-SMA in the cells. Pretreatment with resveratrol （12.5 μmol/L） blocked Ang Ⅱ-induced effects in the cells. UUO induced marked STAT3 phosphorylation, fibronectin, collagen Ⅳ and α-SMA accumulation, and renal interstitial fibrosis in the obstructed kidneys, which were significantly attenuated by daily administration of resveratrol （100 mg/kg）. Conclusion： STAT3 acetylation plays an important role in activation of STAT3 signaling pathway and consequent renal fibrosis.

Background：Src homology 2 domain-containing protein tyrosine phosphatase-2 （SHP-2） is a kind of intracellular protein tyrosine phosphatase.Studies have revealed its roles in various disease,however,whether SHP-2 involves in renal fibrosis remains unclear.The aim of this study was to explore the roles of myeloid cells SHP-2 in renal interstitial fibrosis.Methods：Myeloid cells SHP-2 gene was conditionally knocked-out （CKO） in mice using loxP-Cre system,and renal interstitial fibrosis was induced by unilateral ureter obstruction （UUO）.The total collagen deposition in the renal interstitium was assessed using picrosirius red stain.F4/80 immunostaing was used to evaluate macrophage infiltration in renal tubular interstitium.Quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to analyze the production of cytokines in the kidney.Transferase-mediated dUTP nick-end labeling stain was used to assess the apoptotic renal tubular epithelial cells.Results：Src homology 2 domain-containing protein tyrosine phosphatase-2 gene CKO in myeloid cells significantly reduced collagen deposition in the renal interstitium after UUO.Macrophage infiltration was evidently decreased in renal tubular interstitium of SHP-2 CKO mice.Meanwhile,the production of pro-inflammatory cytokines was significantly suppressed in SHP-2 CKO mice.However,no significant difference was observed in the number of apoptotic renal tubular epithelial cells between wild-type and SHP-2 CKO mice.Conclusions：Our observations suggested that SHP-2 in myeloid cells plays a pivotal role in the pathogenesis of renal fibrosis,and that silencing of SHP-2 gene in myeloid cells may protect renal from inflammatory damage and prevent renal fibrosis after renal injury.

Aim： To study whether activation of TLR9 by CpG-ODN would protect against and/or reverse renal fibrosis. Methods： Animals were treated with CpG-ODN before or after undergoing a unilateral ureteral obstruction （UUO） procedure. The interstitial fibrotic lesions of obstructed kidneys were evaluated using histology and immunohistostaining. The Th2-type cytokine profile and the expression and activity of sma and mad related protein （Smad）3, signal transducers and activators of transcription （Star）3, extra- cellular regulated protein kinases （ERK）, and p38 kinase were determined using RT-PCR or Western blot. Results： The obstructed kidneys displayed a significant increase in interstitial fibrosis, an infiltration of macrophages in the interstitium, and an enhanced expression of Th2 cytokines. Prophylactic application of CpG-ODN （40 ppJkg every 3 days from 2 h before UUO until the 14th day after UUO） suppressed the expression of （x-smooth muscle actin, collagen deposition, and hydroxyproline in the UUO kid- neys of rats. Moreover, CpG-ODN not only decreased the infiltration of macrophages but also inhibited the expression of chemokines CCL2 and CCL5, the Th2 cytokine IL-13, and the profibrogenic cytokines transforming growth factor （TGF）-I31 and plasminogen activator inhibitor （PAl）-1 in UUO kidneys of rats. Importantly, therapeutic administration of CpG-ODN （10 pp=Jmouse, ip, every 3 days from the 4th day to 21st day after UUO） reversed the established renal fibrosis, which was accompanied by significant reductions in the activity of ERK, Smad3, and Stat3 and an increase in the activity of p38 kinase. Conclusion： The activation of TLR9 by CpG-ODN attenuates UUO-induced renal fibrosis by reversing an immunosuppressive microenvironment in the fibrotic renal tissue, which might be a novel therapeutic strategy against fibrotic renal diseases.

The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog（Shh） is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease（CKD）, Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication（EMC）. Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

目的探讨sorafenib减轻肾纤维化的作用及机制。方法用低、中、高剂量sorafenib分别给单侧输尿管梗阻（UUO）模型大鼠灌胃或干预经TGF-β1刺激的NRK-52E细胞。HE染色观察各组肾组织纤维化情况,免疫荧光染色检测肾组织及NRK-52E细胞α-SMA、E-cadherin的表达情况。用流式细胞术测定各组NRK-52E细胞周期。Western blot检测各组NRK-52E细胞中Smad3和p-Smad3的表达变化。结果 HE染色结果显示,与UUO模型组相比,sorafenib治疗组肾间质纤维化明显减轻,小管萎缩、炎细胞浸润较轻（P〈0.05）;与对照组比较,sorafenib治疗组E-cadherin在NRK-52E细胞和肾组织中表达均增加,而α-SMA表达均降低（P〈0.05）;流式细胞术分析发现细胞周期停滞于G0/G1期的细胞数明显增加,而进入G2、S期的细胞数明显减少（P〈0.05）;与对照组比较,sorafenib干预组p-Smad3蛋白在NRK-52E细胞中表达降低,且与sorafenib剂量呈正相关（P〈0.05）。结论 sorafenib具有抗肾脏纤维化作用,主要通过TGF-β/Smad途径发挥作用,可能为治疗肾纤维化提供一种早期干预的新手段。

IgG4相关性疾病（IgG4-related disease,IgG4-RD）的发现可追溯至对自身免疫性胰腺炎（autoimmune pancreatitis,AIP）的研究。AIP首先于1995年由Yoshida等[1]提出,并认为该病的发病机制与自身免疫性因素显著相关。2003年Kamisawa等[2]首次引入IgG4系统性疾病概念后,临床医师对AIP等临床症候群进行了重新审视和深入研究。