活性维生素D与多发性硬化

活性维生系D具有重要的免疫调节作用，它与多发性硬化(Multiple Sclerosis，MS)的发生、发展及预后有着密切的关系，维生系D的活性形式可以预防和治疗MS的动物模型——实验性自身免疫性脑脊髓炎(EAE)。对活性维生素D的深入研究，有望为MS的防治提供更广阔的空间。     

蛋白尿在慢性肾脏病进展中的新认识

慢性肾脏病(chronic kidney disease,CKD)是肾脏结构或功能的不可逆性改变.蛋白尿不仅是大多数CKD患者共同的临床表现,而且在CKD的进行性发展中起重要作用.蛋白尿可通过诱导足细胞损伤和凋亡等导致肾小球硬化;通过直接毒性作用、激活补体和炎性小体、诱导氧化应激、促进凋亡等途径导致肾小管萎缩和间质纤维...     

活性维生素D与多发性硬化

活性维生系D具有重要的免疫调节作用,它与多发性硬化(MultipleSclerosis,MS)的发生、发展及预后有着密切的关系,维生系D的活性形式可以预防和治疗MS的动物模型——实验性自身免疫性脑脊髓炎(EAE)。对活性维生素D的深入研究,有望为MS的防治提供更广阔的空间。     

维生素D3——非糖尿病肾病慢性肾脏病合并糖尿病的预测因子

目的:研究非糖尿病肾病慢性肾脏病(non-diabetes chronic kidney diseases,ND-CKD)3～5期患者合并糖尿病的相关因素,并用体内维生素D3水平来预测其风险.方法:对ND-CKD3～5期患者的糖尿病发生指标和维生素D3水平进行相关性分析,应用多项logistic回归分析,得出不同水平的维生素D3的ND-CKD合并糖尿病的概率值.结果:ND-CKD3～5期患者体内的维生素D3水平和餐后2h血糖有负相关性(r=-0.430,P=2.07×10-5);该人群体内维生素D3在0～99.9,100.0～199.9,200.0～299.9 nmol/L三个水平合并糖尿病的概率分别为0.393,0.227,0.154.结论:维生素D3作为ND-CKD合并糖尿病的预测因子,有一定的临床意义.     

维生素K在慢性肾脏病患者血管钙化中的作用

血管钙化与慢性肾脏病患者心血管疾病死亡率增加密切相关,且患病率高,而现有治疗措施和效果有限。基质γ-羧基谷氨酸蛋白是一种生理性血管钙化抑制因子,其产生生理活性必须有维生素K的参与。补充维生素K可能是防治慢性肾脏病患者血管钙化有效治疗方法,尤其维持性血液透析患者可能普遍存在维生素K缺乏。本文对维生素K在慢性肾脏病患者血管钙化中的作用做一综述。     

半乳糖凝集素-3在慢性肾脏病中的研究进展

慢性肾脏病(chronic kidney disease,CKD)是一个日益严重的健康问题,其特征是肾功能的进行性和不可逆性丧失.随着肾功能下降,CKD患者最终会出现严重的电解质代谢紊乱、全身各系统疾病,甚至危及生命.近年来,半乳糖凝集素-3(galectin-3,Gal-3)作为一种β-半乳糖苷结合蛋白备备受关注.研...     

维生素D研究进展

维生素Ｄ与甲状旁腺激素和降钙素共同组成体内钙代谢的主要调节系统。特别是对维持血钙平衡，维生素Ｄ起着关键作用。作者曾在１９８６年于本刊发表一篇有关维生素Ｄ研究进展的综述。时过１２年后，维生素Ｄ的研究在许多方面又取得很大进展，现作部分简介。一、１，２５一...     

维生素D系统在类风湿关节炎中的作用研究进展

最新研究表明维生素D的缺乏会加速类风湿性关节炎的发生和发展,其通过与维生素D受体(Vitamin D Receptor,VDR)结合而发挥作用,不仅参与机体钙磷代谢、骨盐沉积,而且作用于机体免疫系统,调节免疫细胞的增殖和分化,抑制细胞和体液免疫应答,从而有效的防止炎症性疾病的发生,在治疗和预防类风湿性关节炎方面有着巨大的发展潜力。因此本文就维生素D系统在类风湿性关节炎中作用的研究进展做一综述。     

维生素D在哮喘发病机制中的作用

生素D除了参与钙磷代谢和调节骨骼稳态作用外,还具有调节机体免疫等广泛的生物学调节功能。维生素D不足使免疫细胞增殖和分化偏移而产生异常免疫反应。哮喘是由多种细胞（包括肥大细胞、嗜酸性粒细胞和T淋巴细胞）参与的慢性气道炎症,也是一种由遗传和环境因素共同作用的复杂多基因遗传病。近些年研究表明,维生素D缺乏会增加哮喘易感性和严重程度,与哮喘的遗传和非遗传因素共同参与哮喘的发病。     

维生素D在治疗骨质疏松症中的作用

维生素D主要源于皮肤的合成,目前被认为是一种生理激素,而不是维生素.维生素D缺乏(＜ 50nmol/L)是一个影响人类健康的全球性问题,因其在各种生理系统中起到至关重要的作用.各种研究表明,血清25(OH)D水平高,可降低髋及脊柱骨折的发病率.有关于研究使用治疗剂量维生素D的数据很少,大多数的研究集中在低生理剂量而不是高药理剂量.为了达到75nmol/L的浓度,800～1000IU/天是必需的.未来应该关注将25 (OH) D3维持到75nmol/L,以此增加骨质密度、降低骨折风险,同时在维生素D缺乏的情况下,应用高剂量治疗.根据新的证据表明,维生素D在治疗和补充两个方面需要被重新评估,这需要注意维持血清25(OH)D的水平,为了获得预防骨质疏松症和预期的效果,能够降低骨质疏松性骨折的复发.     

Absence of ULK1 decreases AMPK activity in the kidney,leading to chronic kidney disease progression

AMP-activated protein kinase (AMPK) inactivation in chronic kidney disease (CKD) leads to energy status deterioration in the kidney, constituting the vicious cycle of CKD exacerbation. Unc-51-like kinase 1 (ULK1) is considered a downstream molecule of AMPK; however, it was recently reported that the activity of AMPK could be regulated by ULK1 conversely. We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1^−/− mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1^−/− mice, reduced AMPK and its downstream β-oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1^−/− mice with normal renal function compared to control wild-type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic target for CKD treatment, which regulates AMPK activity in the kidney.     

活性维生素D3对大鼠肺纤维化中蛋白激酶D1介导的抗氧化通路的影响

目的:探讨肺纤维化发生发展中蛋白激酶D1(PKD1)介导的线粒体抗氧化通路的作用以及活性维生素D3在纤维化过程中对该通路的影响。方法:雄性SD大鼠随机分成对照组、模型组和治疗组。应用实时荧光定量PCR和免疫组织化学分别从mRNA和蛋白质水平检测大鼠肺组织中PKD1、核转录因子(NF-κB)和锰超氧化物歧化酶(MnSOD)的表达。结果:在第14天,治疗组和模型组中PKD1、NF-κB和MnSOD的表达量都显著低于对照组,而治疗组中3种因子的表达量又明显高于模型组;在第21天,3种因子在模型组和治疗组中的表达量明显高于对照组。在第28天,3种因子在模型组和治疗组中的表达量与对照组相比两两之间均没有差异。结论:PKD1-MnSOD线粒体抗氧化通路在博莱霉素引起的大鼠肺纤维化早期发挥重要作用,活性维生素D3能够上调这一抗氧化通路,具有一定的抗氧化作用,对大鼠肺纤维化的发生发展具有一定的抑制作用。     

Prevalence and correlates of sleep apnea among US Veterans with chronic kidney disease

The prevalence and correlates of sleep apnea (SA) among Veterans with chronic kidney disease (CKD), a population at high risk of both SA and CKD, are unknown. We performed a cross‐sectional analysis of 248 Veterans (18–89 years) selected only for presence of moderate to severe CKD. All participants underwent full, unattended polysomnography, measurement of renal function and a sleepiness questionnaire. Logistic regression with backward selection was used to identify predictors of prevalent SA (apnea–hypopnea index [AHI, ≥15 events/hr] and prevalent nocturnal hypoxia [NH, % of total sleep time spent at <90% oxygen saturation]). The mean age of our cohort was 73.2 ± 9.6 years, 95% were male, 78% were Caucasian and the mean body mass index (BMI) was 30.3 ± 4.8 kg/m². The prevalence of SA was 39%. There was no difference in daytime sleepiness among those with and without SA. In the final model, older age, higher BMI and diabetes mellitus (DM) were associated with higher odds of SA, after controlling for age, BMI, race and sex. Higher BMI, DM, unemployed/retired status, current smoking and higher serum bicarbonate level were associated with prevalent NH. To sum, SA was common among Veterans with moderate to severe CKD. Although some traditional risk factors for SA were associated with SA in this population, sleepiness did not correlate with SA. Further study is needed to validate our findings and understand how best to address the high burden of SA among Veterans with CKD.     

Endothelial cell plasticity in kidney fibrosis and disease

Renal endothelial cells demonstrate an impressive remodeling potential during angiogenic sprouting, vessel repair or while transitioning into mesenchymal cells. These different processes may play important roles in both renal disease progression or regeneration while underlying signaling pathways of different endothelial cell plasticity routes partly overlap. Angiogenesis contributes to wound healing after kidney injury and pharmaceutical modulation of angiogenesis may home a great therapeutic potential. Yet, it is not clear whether any differentiated endothelial cell can proliferate or whether regenerative processes are largely controlled by resident or circulating endothelial progenitor cells. In the glomerular compartment for example, a distinct endothelial progenitor cell population may remodel the glomerular endothelium after injury. Endothelial-to-mesenchymal transition (EndoMT) in the kidney is vastly documented and often associated with endothelial dysfunction, fibrosis, and kidney disease progression. Especially the role of EndoMT in renal fibrosis is controversial. Studies on EndoMT in vivo determined possible conclusions on the pathophysiological role of EndoMT in the kidney, but whether endothelial cells really contribute to kidney fibrosis and if not what other cellular and functional outcomes derive from EndoMT in kidney disease is unclear. Sequencing data, however, suggest no participation of endothelial cells in extracellular matrix deposition. Thus, more in-depth classification of cellular markers and the fate of EndoMT cells in the kidney is needed. In this review, we describe different signaling pathways of endothelial plasticity, outline methodological approaches and evidence for functional and structural implications of angiogenesis and EndoMT in the kidney, and eventually discuss controversial aspects in the literature.     

胱抑素C评价早中期慢性肾脏病患者肾功能损害的临床价值

目的探讨血清胱抑素C（CysC）评价早中期慢性肾脏病（CKD）患者肾功能损害的临床价值。方法以2008年1月至2010年12月深圳市第六人民医院肾内科住院治疗的221例CKD1～3期患者为观察对象,测定CysC、血肌酐（SCr）、血尿素氮（BUN）、血尿酸（BUA）及血白蛋白（Alb）,与MDRD公式计算的肾小球滤过率（GFR）进行比较。结果 CKD1～3期患者CysC随着GFR的下降而升高,各组间比较差异有统计学意义（P〈0.05）;血清CysC水平与SCr、BUN及BUA水平呈明显正相关（r=0.650,P=0.000;r=0.631,P=0.000;r=0.309,P=0.000）,与GFR水平呈明显负相关（r=-0.717,P=0.000）。CKD2期患者CysC异常检出率为32.8%,SCr为0;CKD3期患者CysC异常检出率为73.0%,SCr为58.4%,CKD3期患者CysC、SCr的异常检出率差异有统计学意义（P〈0.05）。CysC评估GFR的接受者操作特征曲线下面积（AUCROC）为0.853,敏感性为0.780,特异性为0.817;SCr的AUCROC为0.924,敏感性为0.793,特异性为0.958;联合CysC和SCr后,AUCROC上升至0.940,敏感性为0.853,特异性为0.950。结论 CysC是评估早中期CKD患者肾功能损害的敏感指标,联合应用CysC和SCr可提高对早中期慢性肾功能不全患者的诊断效能。     

sTREM‐1 in patients with chronic kidney disease on hemodialysis

The triggering receptor expressed on myeloid cells‐1 (TREM‐1) is a member of the immunoglobulin superfamily. TREM‐1 has been implicated as an amplifier of inflammation. Soluble TREM‐1 (sTREM‐1) was investigated in different clinical conditions, but not in hemodialysis (HD) patients. We aimed to investigate sTREM‐1 as a marker of inflammation in HD patients. We investigated 40 CKD patients undergoing chronic HD treatment and 15 controls. Routine laboratory investigations in addition to CRP measured by immunoturbidimetry, TNF‐ α, and sTREM‐1 measured by ELISA were assayed in post–hemodialysis patients’ blood samples and in controls’ blood samples. CRP, TNF‐α, and sTREM‐1 levels were significantly higher in HD patients than in controls (p < 0.001 for all). sTREM‐1 was positively correlated with CRP and TNF‐α (r = +0.50, p < 0.001 and r = +0.53, p < 0.001 respectively). It was negatively correlated with hemoglobin concentration (r = ?0.69, p < 0.001). Hemoglobin concentration was the significant predictor of sTREM‐1 level (p < 0.001). In conclusion, sTREM‐1 level is significantly increased in HD patients as are other pro‐inflammatory markers.     

Mast cells and inflammatory kidney disease

Summary:  Inflammatory kidney disease involves a complex network of interactions between resident kidney and infiltrating hematopoietic cells. Mast cells (MCs) are constitutively found in kidneys in small numbers but increase considerably in various renal diseases. While this increase is usually interpreted as a sign of pathological involvement, recent data using MC-deficient animals show their ability to restore kidney homeostasis. In anti-glomerular basement membrane antibody-induced glomerulonephritis, MCs are protective by initiating repair and remodeling functions counteracting the devastating effects of glomerular injury. Protection may also include immunoregulatory capacities to limit autoreactive T-cell responses. MCs also control tubulointerstitial fibrosis by activating tissue remodeling and neutralizing fibrotic factors. Release of mediators by MCs during inflammation, however, could also promote unwanted responses that ultimately lead to destruction of kidney structure, as exemplified by data showing either protection or aggravation in related renal disease models. Similarly, while the action of proteases may initially be beneficial, the generation of fibrosis-promoting angiotensin II by chymase also shows the limits of adaptive responses to achieve homeostasis. Thus, it is likely the physiological context involving the interaction with other cells and inflammatory mediators that determines the final action of MCs in the development of kidney disease.     

Clinical application of neutrophil gelatinase-associated lipocalin in the revised chronic kidney disease classification

Background: A revised classification of chronic kidney disease (CKD) was proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2012. Neutrophil gelatinase-associated lipocalin (NGAL) was considered as one of the most promising biomarkers in clinical nephrology. The aim of this study was to examine the level of NGAL in patients with different impairment of GFR based on the new classification, and to evaluate whether NGAL in serum or urine was associated with different risk categories in CKD patients. Methods: A cross-sectional study was performed in 240 patients with CKD. NGAL, serum cystatin C, β₂-macroglobulin (β₂-MG), urine α₁-macroglobulin (α₁-MG) and albuminuria were tested in patients with various degrees of renal impairment. Results: Good correlation was found between the NGAL and the cystatin C, β₂-MG and the α₁-MG (r > 0.7). The level of sNGAL in CKD stage 3b was more than that in CKD stage 3a (P = 0.025). The concentration of the NGAL increased progressively with the increasing of risk categories (proposed by the revised CKD classification). The cutoff value of NGAL was calculated from stage 2 to stage 5. ROC analysis showed good AUC (sNGAL > 0.8, uNGAL > 0.7) and high specificity (sNGAL > 87%, uNGAL > 90%) on the cutoff value of NGAL. Conclusion: The results confirm NGAL as a useful biomarker in clinical nephrology which is helpful to diagnosis and evaluate the categories for CKD proposed by the KDIGO.     

自噬及铁死亡相关靶点与慢性肾病肾功能损伤的进展：生物信息学分析及实验验证

BACKGROUND: Autophagy and ferroptosis play important roles in the development of chronic kidney disease, but the molecular mechanisms and gene targets related to autophagy and ferroptosis in renal tissue of chronic kidney disease are still unclear. OBJECTIVE: To screen differentially expressed genes in chronic kidney disease-related datasets based on bioinformatics, and to explore potential key biomarkers suitable for screening renal function progression in patients with chronic kidney disease. METHODS: (1) The GSE137570 dataset was obtained from GEO database to screen the differentially expressed genes by Networkanalyst database analysis. Ferroptosis and autophagy related targets were obtained by OMIM, GENECARD, FerrDb and HAMdb databases. The respective data were intersected to obtain autophagy-ferroptosis related differentially expressed genes in chronic kidney disease for parallel enrichment analysis. The STRING website was used to construct the protein-protein interaction network of differentially expressed genes, which was imported into Cytoscape software and analyzed by MCODE and Cytohubba plug-in to screen potential core targets. Enrichment analysis was performed to obtain the functions of these potential core targets. (2) In the in vitro experiment, mouse renal tubular epithelial cells were divided into two groups: the control group received no intervention, while the model group was stimulated with 5 ng/mL transforming growth factor β1 for 24 hours to induce mesenchymal transformation of renal tubular epithelial cells. Flow cytometry was used to measure the levels of reactive oxygen species and changes in mitochondrial membrane potential in the cells. RT-PCR was employed to assess ferroptosis, autophagy-related markers, and the mRNA expression of potential core targets in the cells. RESULTS AND CONCLUSION: After screening the GSE137570 dataset, a total of 480 differentially expressed genes were obtained, including 104 upregulated genes and 376 downregulated genes (log2| (FC) | > 1, P < 0.05). There were 562 ferroptosis-related targets and 1 266 autophagy-related targets obtained from the OMIM, GENECARD, FerrDb, and HAMdb databases. Intersection of differentially expressed genes with ferroptosis- and autophagy-related targets yielded 15 ferroptosis-related targets and 18 autophagy-related targets, respectively. The enrichment analysis results indicate that ferroptosis-related differentially expressed genes are primarily involved in biological processes such as sulfur amino acid metabolism, neutrophil degranulation, and ferroptosis signaling pathways. Autophagy-related differentially expressed genes are mainly enriched in biological processes such as platelet degranulation, extracellular matrix degradation, and receptor tyrosine kinase signaling. After screened by MCODE and CytoHubba, key genes were identified in the protein-protein interaction network, including CD44, ALB, TIMP1, PLG, CCL2, and DPP4. Immune infiltration analysis results indicate that immune cells such as B cells, CD4+ T cells, NK cells, and monocytes show significant differential expression in renal tissue after chronic kidney disease, and the core targets are also significantly correlated with these immune cells (P < 0.05). The results of receiver operator characteristic curve analysis further demonstrate that the pathological progression of chronic kidney disease can be effectively diagnosed by CD44, ALB, TIMP1, PLG, CCL2, and DPP4. Single-cell sequencing results show that, except for PLG, the expression of target genes in the renal tissue of mice in each model group is generally consistent with the results of this experiment. RT-PCR results demonstrate that, for the validation of autophagy and ferroptosis phenotypes, compared with the control group, the model group shows a significant decrease in mRNA expression of LC3B, Nrf2, and SLC7A11 (P < 0.05), and a significant increase in P62 mRNA expression (P < 0.05). Regarding the validation of potential core targets, compared with the control group, the model group exhibits a significant decrease in mRNA expression of ALB and PLG (P < 0.05), and a significant increase in TIMP1 and CCL2 mRNA expression (P < 0.05). Overall, these findings indicate that, through bioinformatics analysis and experimental validation, CD44, ALB, TIMP1, PLG, and CCL2 are abnormally expressed in the renal tissue of patients with chronic kidney disease, closely correlated with estimated glomerular filtration rate and tubulointerstitial fibrosis, and maybe play a predictive role in the progression of chronic kidney disease. © 2024, Chinese Journal of Tissue Engineering Research. All rights reserved.     

Normal lymphocyte interferon production in adult HBsAg-positive chronic active liver disease

To challenge the hypothesis that interferon (IF) production in chronic hepatitis-B virus liver disease is defective, lymphocytes from 14 patients with chronic active liver disease (CALD); from nine patients with chronic inactive liver disease (CILD), and from six healthy chronic carriers (HCC) were stimulated by Newcastle Disease virus. The patients with CILD showed a weak IF response by comparison with the controls (P less than 0.0005), whereas IF production by CALD patients and the HCC did not statistically differ from IF production in the healthy hepatitis-B surface antigen negative subjects who served as controls. These results indicate that IF treatment of CALD does not rely on a completely proved background.