ELABELA(ELA),an endogenous ligand of the apelin receptor(also known as apelin peptide jejunum[APJ]),has been shown to decrease in the plasma of patients with diabetic kidney disease(DKD).In the current study,we explor...ELABELA(ELA),an endogenous ligand of the apelin receptor(also known as apelin peptide jejunum[APJ]),has been shown to decrease in the plasma of patients with diabetic kidney disease(DKD).In the current study,we explored the potential function as well as the underlying mechanisms of ELA in DKD.We first found that the ELA levels were decreased in the kidneys of DKD mice.Then,we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin,collagenⅣ,and transforming growth factor-β1 in the db/db mice and the high glucose cultured HK-2 cells.Furthermore,the autophagy markers,Beclin-1 and LC3-Ⅱ/LC3-Ⅰratio,were significantly impaired in DKD,but the ELA treatment reversed these alterations.Mechanistically,the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine(an autophagy inhibitor).In summary,these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy,potentially serving as a novel therapeutic candidate for DKD.展开更多
BACKGROUND Diabetic kidney disease(DKD)is a major complication of diabetes mellitus.Renal tubular epithelial cell(TEC)damage,which is strongly associated with the inflammatory response and mesenchymal trans-differenti...BACKGROUND Diabetic kidney disease(DKD)is a major complication of diabetes mellitus.Renal tubular epithelial cell(TEC)damage,which is strongly associated with the inflammatory response and mesenchymal trans-differentiation,plays a significant role in DKD;However,the precise molecular mechanism is unknown.The recently identified microRNA-630(miR-630)has been hypothesized to be closely associated with cell migration,apoptosis,and autophagy.However,the association between miR-630 and DKD and the underlying mechanism remain unknown.AIM To investigate how miR-630 affects TEC injury and the inflammatory response in DKD rats.METHODS Streptozotocin was administered to six-week-old male rats to create a hypergly cemic diabetic model.In the second week of modeling,the rats were divided into control,DKD,negative control of lentivirus,and miR-630 overexpression groups.After 8 wk,urine and blood samples were collected for the kidney injury assays,and renal tissues were removed for further molecular assays.The target gene for miR-630 was predicted using bioinformatics,and the association between miR-630 and toll-like receptor 4(TLR4)was confirmed using in vitro investigations and double luciferase reporter gene assays.Overexpression of miR-630 in DKD rats led to changes in body weight,renal weight index,basic blood parameters and histopathological changes.RESULTS The expression level of miR-630 was reduced in the kidney tissue of rats with DKD(P<0.05).The miR-630 and TLR4 expressions in rat renal TECs(NRK-52E)were measured using quantitative reverse transcription polymerase chain reaction.The mRNA expression level of miR-630 was significantly lower in the high-glucose(HG)and HG+mimic negative control(NC)groups than in the normal glucose(NG)group(P<0.05).In contrast,the mRNA expression level of TLR4 was significantly higher in these groups(P<0.05).However,miR-630 mRNA expression increased and TLR4 mRNA expression significantly decreased in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Furthermore,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and IL-6 were significantly higher in the HG and HG+mimic NC groups than in NG group(P<0.05).However,the levels of these cytokines were significantly lower in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Notably,changes in protein expression were observed.The HG and HG+mimic NC groups showed a significant decrease in E-cadherin protein expression,whereas TLR4,α-smooth muscle actin(SMA),and collagen IV protein expression increased(P<0.05).Conversely,the HG+miR-630 mimic group exhibited a significant increase in E-cadherin protein expression and a notable decrease in TLR4,α-SMA,and collagen IV protein expression than in the HG+mimic NC group(P<0.05).The miR-630 targets TLR4 gene expression.In vivo experiments demonstrated that DKD rats treated with miR-630 agomir exhibited significantly higher miR-630 mRNA expression than DKD rats injected with agomir NC.Additionally,rats treated with miR-630 agomir showed significant reductions in urinary albumin,blood glucose,TLR4,and proinflammatory markers(TNF-α,IL-1β,and IL-6)expression levels(P<0.05).Moreover,these rats exhibited fewer kidney lesions and reduced infiltration of inflammatory cells.CONCLUSION MiR-630 may inhibit the inflammatory reaction of DKD by targeting TLR4,and has a protective effect on DKD.展开更多
Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and...Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC.展开更多
IgA肾病(immunoglobulin A nephropathy,IgAN)属于常见的原发性肾小球肾炎之一,也是终末期肾病(end-stage renal disease,ESRD)的主要病因之一。IgAN的治疗仍然存在挑战,干预相关的危险因素,可延缓疾病的进展。近年发现,高尿酸血症是IgA...IgA肾病(immunoglobulin A nephropathy,IgAN)属于常见的原发性肾小球肾炎之一,也是终末期肾病(end-stage renal disease,ESRD)的主要病因之一。IgAN的治疗仍然存在挑战,干预相关的危险因素,可延缓疾病的进展。近年发现,高尿酸血症是IgAN患者常见的临床特点,也是疾病进展的危险因素之一,但高尿酸血症与IgAN病理改变及疾病进展的关系仍不明确。因此,明确高尿酸血症与IgAN的关系具有重要的临床意义。本文从高尿酸血症在IgAN中的患病率、相关的发病机制与IgAN进展的关系及治疗靶点等方面进行了较为详尽的综述。展开更多
目的 探讨当归芍药散(DSS)含药血清及其有效成分阿魏酸(FA)、芍药苷(PF)对肾间质纤维化(RIF)大鼠的作用及机制。方法 制备当归芍药散药液,以低剂量(0.05 mL DSS药液/10 g体质量)、中剂量(0.1 mL DSS药液/10 g体质量)、高剂量(0.2 mL DS...目的 探讨当归芍药散(DSS)含药血清及其有效成分阿魏酸(FA)、芍药苷(PF)对肾间质纤维化(RIF)大鼠的作用及机制。方法 制备当归芍药散药液,以低剂量(0.05 mL DSS药液/10 g体质量)、中剂量(0.1 mL DSS药液/10 g体质量)、高剂量(0.2 mL DSS药液/10 g体质量)每日同一时间灌胃雄性Sprague Dawley大鼠,持续7 d,腹主动脉取血获得相应低、中、高剂量DSS血清(DSSS)。将大鼠肾小管上皮细胞(NRK-52E)分成对照组、模型组(TGF-β处理)、siRNA转染组(TGF-β+siRNA处理)、FA组(TGF-β+FA处理)、PF组(TGF-β+PF处理)及DSSS低、中、高剂量组(TGF-β+DSSS-L、TGF-β+DSSS-M、TGF-β+DSSS-H分别处理)。筛选并确定DSSS、FA、PF、TGF-β对NRK-52E细胞的干预浓度,对以上各组NRK-52E细胞进行干预。采用Western blotting法检测各组NLRP3、半胱氨酸蛋白酶1(CASP-1)、Gasdermin D(GSDMD)、白细胞介素-18(IL-18)、纤连蛋白(FN)、E型钙黏蛋白(E-Cadherin)、N型钙黏蛋白(N-Cadherin)的蛋白表达变化。结果 相较于模型组,DSSS、FA、PF治疗组细胞焦亡相关蛋白NLRP3、CASP-1、GSDMD、IL-18表达均降低,差异均有统计学意义(P均<0.05)。DSSS中、高剂量及FA、PF治疗组相较于模型组纤维化相关黏附蛋白FN、E-Cadherin、N-Cadherin表达降低,差异均有统计学意义(P均<0.05)。结论 当归芍药散含药血清及有效成分FA、PF可抑制TGF-β诱导的NRK-52E细胞纤维化模型中NLRP3介导的焦亡蛋白激活,并能调节黏附蛋白表达和上皮-间质转化进展,缓解纤维化。展开更多
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82000743 and 81700723)the Jiangsu Natural Science Foundation(Grant No.BK20191213).
文摘ELABELA(ELA),an endogenous ligand of the apelin receptor(also known as apelin peptide jejunum[APJ]),has been shown to decrease in the plasma of patients with diabetic kidney disease(DKD).In the current study,we explored the potential function as well as the underlying mechanisms of ELA in DKD.We first found that the ELA levels were decreased in the kidneys of DKD mice.Then,we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin,collagenⅣ,and transforming growth factor-β1 in the db/db mice and the high glucose cultured HK-2 cells.Furthermore,the autophagy markers,Beclin-1 and LC3-Ⅱ/LC3-Ⅰratio,were significantly impaired in DKD,but the ELA treatment reversed these alterations.Mechanistically,the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine(an autophagy inhibitor).In summary,these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy,potentially serving as a novel therapeutic candidate for DKD.
基金Supported by the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China,No.LHDMZ22H050001the Construction of Key Projects by Zhejiang Provincial Ministry,No.WKJ-ZJ-2302+3 种基金the Zhejiang Province Chinese Medicine Modernization Program,No.2020ZX001the Key Project of Scientific Research Foundation of Chinese Medicine,No.2022ZZ002the“Pioneer”and“LeadingGoose”R&D Program of Zhejiang,No.2022C03118 and 2023C03075the Key Project of Basic Scientific Research Operating Funds of Hangzhou Medical College,No.KYZD202002.
文摘BACKGROUND Diabetic kidney disease(DKD)is a major complication of diabetes mellitus.Renal tubular epithelial cell(TEC)damage,which is strongly associated with the inflammatory response and mesenchymal trans-differentiation,plays a significant role in DKD;However,the precise molecular mechanism is unknown.The recently identified microRNA-630(miR-630)has been hypothesized to be closely associated with cell migration,apoptosis,and autophagy.However,the association between miR-630 and DKD and the underlying mechanism remain unknown.AIM To investigate how miR-630 affects TEC injury and the inflammatory response in DKD rats.METHODS Streptozotocin was administered to six-week-old male rats to create a hypergly cemic diabetic model.In the second week of modeling,the rats were divided into control,DKD,negative control of lentivirus,and miR-630 overexpression groups.After 8 wk,urine and blood samples were collected for the kidney injury assays,and renal tissues were removed for further molecular assays.The target gene for miR-630 was predicted using bioinformatics,and the association between miR-630 and toll-like receptor 4(TLR4)was confirmed using in vitro investigations and double luciferase reporter gene assays.Overexpression of miR-630 in DKD rats led to changes in body weight,renal weight index,basic blood parameters and histopathological changes.RESULTS The expression level of miR-630 was reduced in the kidney tissue of rats with DKD(P<0.05).The miR-630 and TLR4 expressions in rat renal TECs(NRK-52E)were measured using quantitative reverse transcription polymerase chain reaction.The mRNA expression level of miR-630 was significantly lower in the high-glucose(HG)and HG+mimic negative control(NC)groups than in the normal glucose(NG)group(P<0.05).In contrast,the mRNA expression level of TLR4 was significantly higher in these groups(P<0.05).However,miR-630 mRNA expression increased and TLR4 mRNA expression significantly decreased in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Furthermore,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and IL-6 were significantly higher in the HG and HG+mimic NC groups than in NG group(P<0.05).However,the levels of these cytokines were significantly lower in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Notably,changes in protein expression were observed.The HG and HG+mimic NC groups showed a significant decrease in E-cadherin protein expression,whereas TLR4,α-smooth muscle actin(SMA),and collagen IV protein expression increased(P<0.05).Conversely,the HG+miR-630 mimic group exhibited a significant increase in E-cadherin protein expression and a notable decrease in TLR4,α-SMA,and collagen IV protein expression than in the HG+mimic NC group(P<0.05).The miR-630 targets TLR4 gene expression.In vivo experiments demonstrated that DKD rats treated with miR-630 agomir exhibited significantly higher miR-630 mRNA expression than DKD rats injected with agomir NC.Additionally,rats treated with miR-630 agomir showed significant reductions in urinary albumin,blood glucose,TLR4,and proinflammatory markers(TNF-α,IL-1β,and IL-6)expression levels(P<0.05).Moreover,these rats exhibited fewer kidney lesions and reduced infiltration of inflammatory cells.CONCLUSION MiR-630 may inhibit the inflammatory reaction of DKD by targeting TLR4,and has a protective effect on DKD.
文摘Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC.
文摘IgA肾病(immunoglobulin A nephropathy,IgAN)属于常见的原发性肾小球肾炎之一,也是终末期肾病(end-stage renal disease,ESRD)的主要病因之一。IgAN的治疗仍然存在挑战,干预相关的危险因素,可延缓疾病的进展。近年发现,高尿酸血症是IgAN患者常见的临床特点,也是疾病进展的危险因素之一,但高尿酸血症与IgAN病理改变及疾病进展的关系仍不明确。因此,明确高尿酸血症与IgAN的关系具有重要的临床意义。本文从高尿酸血症在IgAN中的患病率、相关的发病机制与IgAN进展的关系及治疗靶点等方面进行了较为详尽的综述。
