scholarly journals Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease

2019 ◽  
Vol 30 (4) ◽  
pp. 533-545 ◽  
Author(s):  
Jia Fu ◽  
Kemal M. Akat ◽  
Zeguo Sun ◽  
Weijia Zhang ◽  
Detlef Schlondorff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kidney Disease ◽  
Immune Cells ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Specific Gene ◽  
Dynamic Changes ◽  
Glomerular Cell ◽  
Diabetic Kidney ◽  
And Control

BackgroundRecent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited.MethodsTo elucidate the glomerular cell–specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)–deficient (eNOS−/−) mice and control eNOS−/− mice.ResultsWe identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell–specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury.ConclusionsOur findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.

scholarly journals Glomerular endothelial cell injury and cross talk in diabetic kidney disease

2015 ◽  
Vol 308 (4) ◽  
pp. F287-F297 ◽  
Author(s):  
Jia Fu ◽  
Kyung Lee ◽  
Peter Y. Chuang ◽  
Zhihong Liu ◽  
John Cijiang He
Keyword(s):  
Endothelial Cell ◽  
Kidney Disease ◽  
Cross Talk ◽  
Diabetic Kidney Disease ◽  
Cell Injury ◽  
Mesangial Cells ◽  
Glomerular Endothelial Cell ◽  
Glomerular Cell ◽  
Diabetic Kidney ◽  
Endothelial Cell Surface

Diabetic kidney disease (DKD) remains a leading cause of new-onset end-stage renal disease (ESRD), and yet, at present, the treatment is still very limited. A better understanding of the pathogenesis of DKD is therefore necessary to develop more effective therapies. Increasing evidence suggests that glomerular endothelial cell (GEC) injury plays a major role in the development and progression of DKD. Alteration of the glomerular endothelial cell surface layer, including its major component, glycocalyx, is a leading cause of microalbuminuria observed in early DKD. Many studies suggest a presence of cross talk between glomerular cells, such as between GEC and mesangial cells or GEC and podocytes. PDGFB/PDGFRβ is a major mediator for GEC and mesangial cell cross talk, while vascular endothelial growth factor (VEGF), angiopoietins, and endothelin-1 are the major mediators for GEC and podocyte communication. In DKD, GEC injury may lead to podocyte damage, while podocyte loss further exacerbates GEC injury, forming a vicious cycle. Therefore, GEC injury may predispose to albuminuria in diabetes either directly or indirectly by communication with neighboring podocytes and mesangial cells via secreted mediators. Identification of novel mediators of glomerular cell cross talk, such as microRNAs, will lead to a better understanding of the pathogenesis of DKD. Targeting these mediators may be a novel approach to develop more effective therapy for DKD.

scholarly journals miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mitsuo Kato ◽  
Maryam Abdollahi ◽  
Ragadeepthi Tunduguru ◽  
Walter Tsark ◽  
Zhuo Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Mitochondrial Fission ◽  
Major Complication ◽  
Body Weight Loss ◽  
Diabetic Kidney ◽  
Guide Rna ◽  
And Oxidative Stress

AbstractDiabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.

scholarly journals BKCa Mediates Dysfunction in High Glucose Induced Mesangial Cell Injury via TGF-β1/Smad2/3 Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhigui Wu ◽  
Wenxian Yin ◽  
Mengqi Sun ◽  
Yuankai Si ◽  
Xiaoxiao Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Kidney

Objective. To explore the role and mechanism of BKCa in diabetic kidney disease. Methods. Rat mesangial cells (MCs) HBZY-1 were cultured with high glucose to simulate the high-glucose environment of diabetic kidney disease in vivo. The effects of large conductance calcium-activated potassium channel (BKCa) on proliferation, migration, and apoptosis of HBZY-1 cells were observed. The contents of transforming growth factor beta 1 (TGF-β1), Smad2/3, collagen IV (Col IV), and fibronectin (FN) in the extracellular matrix were also observed. Results. High glucose significantly damaged HBZY-1 cells, which enhanced the ability of cell proliferation, migration, and apoptosis, and increased the secretion of Col IV and FN. Inhibition of BKCa and TGF-β1/Smad2/3 signaling pathways can inhibit the proliferation, migration, and apoptosis of HBZY-1 cells and suppress the secretion of Col IV and FN. The effect of excitation is the opposite. Conclusions. BKCa regulates mesangial cell proliferation, migration, apoptosis, and secretion of Col IV and FN and is associated with TGF-β1/Smad2/3 signaling pathway.

scholarly journals Suppressed ER‐associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease

2020 ◽  
Vol 34 (11) ◽  
pp. 15577-15590
Author(s):  
Daisuke Fujimoto ◽  
Takashige Kuwabara ◽  
Yusuke Hata ◽  
Shuro Umemoto ◽  
Tomoko Kanki ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cross Talk ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Podocyte Injury ◽  
Diabetic Kidney

scholarly journals A hyaluronan synthesis inhibitor delays progression of diabetic kidney disease in a mouse experimental model

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004642020
Author(s):  
Guillermo Selman ◽  
Laisel Martinez ◽  
Andrea Lightle ◽  
Alejandra Aguilar ◽  
Daniel Woltmann ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Plasma Glucose ◽  
Diabetic Kidney Disease ◽  
Control Diet ◽  
Experimental Period ◽  
Glomerular Injury ◽  
Synthesis Inhibitor ◽  
Diabetic Kidney ◽  
Injury Index ◽  
And Control

Background: The role of hyaluronan (HA) in the development and progression of diabetic kidney disease (DKD), as well as the precise mechanisms and consequences of HA involvement in this pathology are still to be clarified. Methods: In this study, we assayed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on the development of DKD. Diabetic type 2 model mice (eNOS-/- C57BLKS/Jdb) were fed artificial diets containing 5% 4-MU or not for 9 weeks. Plasma glucose, glomerular filtration rate (GFR), albumin to creatinine ratio (ACR), and biomarkers of kidney function and systemic inflammation were measured at baseline and after treatment. Diabetic nephropathy was further characterized in treated and control mice by histopathology. Results: Treated animals consumed a daily dose of approximately 6.2 g of 4-MU per kg of body weight. At the end of the experimental period, the 4-MU supplemented diet resulted in a significant decrease in non-fasting plasma glucose (516 [interquartile range 378-1170] vs. 1149 [875.8-1287] mg/dL, P=0.050) and a trend toward lower HA kidney content (5.6 ± 1.5 vs. 8.8 ± 3.1 ng/mg of kidney weight, P=0.070) compared to the control diet, respectively. Diabetic animals treated with 4-MU showed significantly higher GFR and lower urine ACR and plasma cystatin C levels than diabetic controls. Independent histological assessment of DKD also demonstrated a significant decrease in mesangial expansion score and glomerular injury index in 4-MU-treated mice compared to controls. Plasma glucose showed a strong correlation with kidney HA levels (r=0.66, P=0.0098). Both total hyaluronan (r=0.76, P=0.0071) and low-molecular-weight hyaluronan content (r=0.64, P=0.036) in the kidneys correlated with urine ACR in mice. Conclusion: These results show that the hyaluronan synthesis inhibitor 4-MU effectively slowed the progression of DKD and constitutes a potential new therapeutic approach to treat DKD.

scholarly journals The Efficacy and Mechanism of Chinese Herbal Medicine on Diabetic Kidney Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Zhenzhen Lu ◽  
Yifei Zhong ◽  
Wangyi Liu ◽  
Ling Xiang ◽  
Yueyi Deng
Keyword(s):  
Kidney Disease ◽  
Herbal Medicine ◽  
Chinese Herbal Medicine ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Symptom Relief ◽  
Glomerular Sclerosis ◽  
Diabetic Kidney ◽  
Chinese Herbal ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes and is one of the main causes of end-stage renal disease (ESRD) in many countries. The pathological features of DKD are the hypertrophy of mesangial cells, apoptosis of podocytes, glomerular basement membrane (GBM) thickening, accumulation of extracellular matrix (ECM), glomerular sclerosis, and tubulointerstitial fibrosis. The etiology of DKD is very complicated and many factors are involved, such as genetic factors, hyperglycemia, hypertension, hyperlipidemia, abnormalities of renal hemodynamics, and metabolism of vasoactive substances. Although some achievements have been made in the exploration of the pathogenesis of DKD, the currently available clinical treatment methods are still not completely effective in preventing the progress of DKD to ESRD. CHM composed of natural products has traditionally been used for symptom relief, which may offer new insights into therapeutic development of DKD. We will summarize the progress of Chinese herbal medicine (CHM) in the treatment of DKD from two aspects. In clinical trials, the Chinese herbal formulas were efficacy and safety confirmed by the randomized controlled trials. In terms of experimental research, studies provided evidence for the efficacy of CHM from the perspectives of balancing metabolic disorders, reducing inflammatory response and oxidative stress, antifibrosis, protecting renal innate cells, and regulating microRNA and metabolism. CHM consisting of different ingredients may play a role in synergistic interactions and multiple target points in the treatment of DKD.

scholarly journals Correlations between SIRT1 gene polymorphisms and diabetic kidney disease

2018 ◽  
Vol 5 (6) ◽  
pp. 171871 ◽  
Author(s):  
Xin-Ge Yue ◽  
Zai-Gang Yang ◽  
Yue Zhang ◽  
Gui-Jun Qin ◽  
Fei Liu
Keyword(s):  
Kidney Disease ◽  
Gene Polymorphisms ◽  
Diabetic Kidney Disease ◽  
Susceptibility Gene ◽  
Albumin Excretion Rate ◽  
Control Group ◽  
Diabetic Kidney ◽  
Significant Difference ◽  
Sirt1 Gene ◽  
And Control

To investigate the correlations between SIRT1 gene polymorphisms and diabetic kidney disease (DKD). There were 150 patients with DKD in the observation group (urinary albumin excretion rate (UAER) ≥ 300 mg 24 h −1 ), and 160 patients with a more than 10 year history of type 2 diabetes but without retinopathy and DKD (UAER < 30 mg 24 h −1 ) in the control group. Genotypes of three tagged single-nucleotide polymorphism loci (rs3818292, rs4746720 and rs10823108) in the SIRT1 gene in the two groups were detected. Risks of DKD for patients with the GG and GG + AG genotype in the rs10823108 locus of the SIRT1 gene were 2.96 and 2.92 times higher than that for AA genotype carriers, respectively. The risk of DKD for patients with the GG genotype in the rs3818292 locus was 0.23 times and 0.21 times higher than that for AA and for AA + AG genotype carriers, respectively, and the risk of DKD for patients with allele G was 0.66 times higher than that for allele A carriers. There was no significant difference in genotype frequency of rs4746720 locus gene polymorphisms between the observation and control groups. The SIRT1 gene is a genetic susceptibility gene of DKD. Mutation genotype GG and GG + AG in the rs10823108 locus can increase the risk of DKD. Mutation genotype GG and allele G in the rs3818292 locus can decrease the risk of DKD.

scholarly journals ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells

2019 ◽  
Vol 317 (4) ◽  
pp. F839-F851 ◽  
Author(s):  
Yosuke Nagai ◽  
Keiichiro Matoba ◽  
Daiji Kawanami ◽  
Yusuke Takeda ◽  
Tomoyo Akamine ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Rho Kinase ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Diabetic Glomerulosclerosis ◽  
Diabetic Kidney

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db/ db mice demonstrated increased gene expression of transforming growth factor (TGF)-β and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db/ db mice was elevated compared with control db/ m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db/ db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.

scholarly journals Extracellular vesicle-derived AEBP1 mRNA as a novel candidate biomarker for diabetic kidney disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yiying Tao ◽  
Xing Wei ◽  
Yue Yue ◽  
Jiaxin Wang ◽  
Jianzhong Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Tissue ◽  
Extracellular Vesicle ◽  
Clinical Parameter ◽  
Diagnostic Efficacy ◽  
Diabetic Kidney ◽  
Efficacy Assessment ◽  
Novel Biomarkers ◽  
And Control

Abstract Background A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. Methods Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. Results Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. Conclusions Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.

Sign in / Sign up

Export Citation Format

Share Document