Human glomerular transcriptome of diabetic kidneys: Can the podocyte cytoskeleton be a therapeutic target?
Human glomerular transcriptome of diabetic kidneys: Can the podocyte cytoskeleton be a therapeutic target?
复制标题
糖尿病肾脏的人肾小球转录组：足细胞细胞骨架可以成为治疗靶标吗？
DOI：
10.1111/jdi.12951
复制
发表时间：
2019-03
影响因子：
3.2
通讯作者：
Yokote K
中科院分区：
文献类型：
--
作者：
Maezawa Y;Yokote K
糖尿病肾病是日本终末期肾衰竭的主要原因。阐明其详细的发病机制和治疗方法的发展是迫切的问题。在《美国肾脏病学会杂志》的这篇文章中，Pan等人1展示了加权基因共表达网络分析（WGCNA）的有用性，并确定了调节糖尿病肾病的潜在重要候选分子。Pan等1通过显微切割从41名糖尿病肾病患者和20名健康个体的肾活检标本中分离肾小球并分析基因表达谱。此外，他们使用包括白蛋白尿和估计的肾小球滤过率在内的临床信息以及表达谱进行了WGCNA，并鉴定了18个共表达基因模块。对与估计的肾小球滤过率和白蛋白尿最相关的基因模块的分析确定了足细胞中表达的细胞骨架调节因子Slit-Robo Rho-鸟苷三磷酸酶（qGTdR）激活蛋白2a（SRGAP 2a）作为与临床数据最相关的候选基因，并作为各种基因表达变化的中心。他们继续通过使用培养的足细胞，小鼠和斑马鱼模型对SRGAP 2a进行功能分析，并表明SRGAP 2a在糖尿病条件下以保护性方式在足细胞中起作用（图1）。据我们所知，Susztak等人于2004年发表了关于糖尿病肾病转录组分析的第一份报告。2使用全肾微阵列分析，他们分别在db/db小鼠和链脲佐菌素诱导的糖尿病小鼠中鉴定出303和272个基因发生改变。在该研究之后，几项研究报告了转录组分析，包括使用啮齿动物糖尿病模型的微阵列或核糖核酸测序。最近，对小鼠的研究利用了细胞分离技术，并报道了特定细胞类型的转录组或甚至单细胞分析。这些研究包括糖尿病小鼠的肾小球内皮细胞、正常小鼠的壁上皮细胞或系膜细胞的单细胞分析。这些进展提供了大量关于每种细胞类型中特定途径的知识，以及即使在一种细胞类型中基因表达的变化。相比之下，已知小鼠和人类糖尿病是不同的。Hodgin等3比较了人糖尿病、链脲佐菌素诱导的糖尿病小鼠、db/db和db/db+内皮型一氧化氮合酶敲除小鼠的肾小球表达谱，在277个改变的基因中，只有26个共同的可变基因。因此，除了复杂的啮齿动物研究外，直接评价人体样本也至关重要。在这方面，Woroniecka等人4在2011年从糖尿病肾脏样本中采集了肾小球和肾小管。在芯片和通路分析中，大鼠肉瘤同源基因家族成员A（RhoA），细胞分裂周期42，整合素和血管内皮生长因子信号突出显示在肾小球。在肾小管间质区，炎症相关通路丰富，表明疾病进展的机制
Diabetic nephropathy is the leading cause of end-stage renal failure in Japan. Clarification of its detailed pathogenesis and development of therapeutic methods are urgent issues. In this article in the Journal of the American Society of Nephrology, Pan et al. 1 showed the usefulness of weighted gene co-expression network analysis (WGCNA) and identified potentially important candidate molecules that regulate diabetic nephropathy. Pan et al. 1 isolated glomeruli from renal biopsy specimens of 41 diabetic nephropathy patients and 20 healthy individuals by microdissection and analyzed gene expression profiles. Furthermore, they carried out WGCNA using clinical information including albuminuria and the estimated glomerular filtration ratio together with the expression profile, and identified 18 co-expression gene modules. Analysis of the gene module that is most correlated with the estimated glomerular filtration ratio and albuminuria identified a cytoskeleton regulator expressed in podocytes, Slit-Robo Rho-guanosine triphosphatase (qGTPase)-activating protein 2a (SRGAP2a), as a candidate gene that correlates most with clinical data and works as a hub of various gene expression changes. They continued to carry out the functional analysis for SRGAP2a by using cultured podocytes, mice and zebrafish models, and showed that SRGAP2a works in a protective manner in podocytes under diabetic conditions (Figure 1). To the best of our knowledge, the first report on transcriptome analysis of diabetic nephropathy was published in 2004 by Susztak et al. 2 Using microarray analysis of whole kidneys, they identified 303 and 272 genes that were altered in db/db mice and streptozotocin-induced diabetic mice, respectively. After that study, several studies reported transcriptome analyses including microarray or ribonucleic acid sequencing using rodent diabetes models. Recently, studies on mice took advantage of cell isolation techniques and reported transcriptomes of specific cell types or even single cell analysis. These include gene expression profiling of isolated glomerular endothelium from diabetic mice, parietal epithelium or single cell analysis of mesangial cells in normal mice. These advances have provided enormous knowledge on the involvement of specific pathways in each cell type, and also the variation of gene expressions even within one cell type.In contrast, it is known that mouse and human diabetes are different. Hodgin et al. 3 compared glomerular expression profiles with human diabetes, streptozotocin-induced diabetic mice, db/db and db/db+ endothelial nitric oxide synthase knockout mice, and among 277 altered genes there were just 26 common variable genes. Therefore, in addition to sophisticated rodent studies, direct evaluation of human samples is critically important. In this regard, Woroniecka et al. 4 collected glomeruli and tubules from diabetic kidney samples in 2011. In microarray and pathway analysis, rat sarcoma homolog gene family member A (RhoA), cell division cycle 42, integrin and vascular endothelial growth factor signaling were highlighted in glomeruli. In the tubulointerstitial compartment, inflammationrelated pathways were enriched, indicating that the mechanisms of disease progression
登录
查看更多内容
影响因子：
19.6
作者：
Verzola, D.;Gandolfo, M. T.;Garibotto, G.
通讯作者：
Garibotto, G.
影响因子：
7.7
作者：
Hodgin JB;Nair V;Zhang H;Randolph A;Harris RC;Nelson RG;Weil EJ;Cavalcoli JD;Patel JM;Brosius FC 3rd;Kretzler M
通讯作者：
Kretzler M
影响因子：
7.7
作者：
Woroniecka KI;Park AS;Mohtat D;Thomas DB;Pullman JM;Susztak K
通讯作者：
Susztak K
影响因子：
3.2
作者：
Coward R;Fornoni A
通讯作者：
Fornoni A
影响因子：
6.1
作者：
Nakamura, T;Ushiyama, C;Koide, H
通讯作者：
Koide, H