scholarly journals Autocrine Exosomal Fibulin-1 as a Target of MiR-1269b Induces Epithelial–Mesenchymal Transition in Proximal Tubule in Diabetic Nephropathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yi-Chun Tsai ◽  
Wei-Wen Hung ◽  
Wei-An Chang ◽  
Ping-Hsun Wu ◽  
Ling-Yu Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial Mesenchymal Transition ◽  
Cell Communication ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Mesenchymal Transition ◽  
Type 2 Diabetic

Background: Diabetic nephropathy (DN) is an increasing threat to human health and is regarded to be the leading cause of end-stage renal disease worldwide. Exosomes deliver biomolecule massages and may play a key role in cell communication and the progression of DN.Methods: A cross-disciplinary study, including in vivo, in vitro, and human studies, was conducted to explore the cross-talk within proximal tubular epithelial cells (PTECs) in DN. Exosomal protein from PTECs treated with high glucose (HG) was purified and examined using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Next-generation sequencing (NGS) was utilized to analyze RNAs extracted from PTECs from a type 2 diabetic patient and a normal individual. HK-2 cells were used to assess exosomal protein and its modulation and biofunction in DN. Normal individuals and type 2 diabetic patients were enrolled, and nondiabetic db/m mice and diabetic db/db mice were used to validate the molecular mechanism of exosomes in DN.Results: HG stimulated PTECs to increase Fibulin-1 (FBLN1) expression, and PTECs secreted FBLN1 through exosome delivery, thereby inducing epithelial–mesenchymal transition (EMT) in PTECs. Transcriptome analysis found that FBLN1 expression was modulated by miR-1269b, which was downregulated by HG in HK-2 cells. While transfection of miR-1269b reversed FBLN1-mediated EMT in PTECs, miR-1269b inhibitor modulated the phenotype of PTECs toward mesenchymal type under normal glucose (NG) condition. Most importantly, urinary FBLN1 and exosomal miR-1269b levels were correlated with the severity of kidney injury in type 2 diabetic patients.Conclusion: This study demonstrated the communication within PTECs through exosome transmission in an autocrine pattern. MiR-1269b–FBLN1 epigenetic regulatory network could be a potential therapeutic strategy to prevent the progression of DN.

scholarly journals The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy

2018 ◽  
Vol 7 (12) ◽  
pp. 468 ◽  
Author(s):  
Yi-Chun Tsai ◽  
Po-Lin Kuo ◽  
Mei-Chuan Kuo ◽  
Wei-Wen Hung ◽  
Ling-Yu Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanisms ◽  
Human Study ◽  
Cell Senescence ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Bioinformatics Analyses ◽  
Type 2 Diabetic

Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.

P0970EXOSOMAL MIR-92A-1-5P DERIVED FROM PROXIMAL TUBULAR EPITHELIAL CELLS INDUCES EPITHELIAL-MESENCHYMAL TRANSITION IN MESANGIAL CELLS IN DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yi-Chun Tsai ◽  
Mei-Chuan Kuo ◽  
Ya-Ling Hsu
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mesangial Cells ◽  
Normal Individual ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Mesenchymal Transition ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Type 2 Diabetic

Abstract Background and Aims Diabetic nephropathy (DN) has been the leading cause of end-stage renal disease in the world-wide. Exosomes play a key role in signal transduction between cell-cell communication in kidney pathophysiology. The aim of this study is to investigate that HK-2 cells-derived exosomal miR-92a-1-5p causes epithelial-mesenchymal transition (EMT) in mesangial cells (MCs), further leading to DN progression. Method The function of HK-2 cells-derived exosomes under normal glucose (NG) and high glucose (HG) was analyzed in mouse MCs model. Total RNAs were extracted from renal proximal tubular epithelial cells (RPTECs) of normal individual and type 2 diabetes for small RNA expression profiling using next-generation sequencing (NGS), then analyzed using systematic bioinformatics analyses. The expression of miR-92a-1-5p was examined in HK-2 cells-derived exosomes and MCs treated with HK-2 cells-derived exosomes under HG. The role of miR-92a-1-5p in EMT was evaluated using MCs model under NG and HG conditions. Urinary exosomal miR-92a-1-5p levels were measured in 50 type 2 diabetic patients and 34 healthy volunteers who were enrolled to determine the relationship between urinary exosomal miR-92a-1-5p and kidney function. Results Decreased E-cadherin, and increased N-cadherin and Vimentin expression were found in mouse MCs treated with HK-2 cells-derived exosomes under HG. Transcriptome analysis of RPTECs of normal individual and type 2 diabetic patient indicated that miR-92a-1-5p contributes to HG-induced renal proliferation. HG elevated miR-92a-1-5p expression in HK-2 cells and exosomes derived from-HK-2 cells, at meanwhile exosomal miR-92a-1-5p derived from-HK-2 cells under HG leads to EMT in mouse MCs. miR-92a-1-5p mimic increased EMT in mouse MCs under NG, and miR-92a-1-5p inhibitor reversed EMT in mouse MCs induced by exosomes derived from HK-2 cells under HG. EMT of mouse MCs was enhanced in the presence of exosomes isolated from the urine of type 2 diabetic patients with high levels of exosomal miR-92a-1-5p. Type 2 diabetic patients had higher urinary exosomal miR-92a-1-5p levels than normal individuals. Higher urinary exosomal miR-92a-1-5p levels were significantly correlated with lower renal function and higher albuminuria in human model. Conclusion Exosomal miR-92a-1-5p derived from HK-2 cells under HG induces EMT in mesangial cells. Blocking miR-92a-1-5p epigenetic regulatory network might be a potential therapeutic strategy to prevent EMT in DN.

Evaluation of urinary TNF-α and KIM-1 biomarkers in T2DM in Upper Egypt

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Magdy EL Sharkawy ◽  
Samir K Abdul-Hamid ◽  
Tarek T Elmelegy ◽  
Mohammed F Adawy
Keyword(s):  
Diabetic Nephropathy ◽  
Early Stage ◽  
Clinical Syndrome ◽  
Diabetic Patients ◽  
University Hospitals ◽  
Type 2 Diabetic Patients ◽  
Cross Sectional ◽  
Tnf Α ◽  
Type 2 Diabetic

Abstract Background Diabetes mellitus (DM) is the most frequent cause of chronic kidney failure in both developed and developing countries. Diabetic nephropathy, is a clinical syndrome characterized by albuminuria (>300 mg/day) with permanent and irreversible decrease in glomerular filtration rate (GFR). Aim of the Work To study the role of urinary TNF-α and urine KIM-1 in type 2 diabetic patients as predictors of DN comparative with albuminuria. Patients and Methods This is a cross-sectional study which include 90 type-2 diabetic patients and 30 controls selected from the outpatient clinic of Assiut University hospitals. All patients gave an informed consent and approval for the study was obtained from the IRB committee of the Assiut Medical Faculty. The recruited patients were divided into three groups: Normo-albuminuria Group (A) (n = 30): UACR less than 30 mg/gm, Microalbuminuria Group (B) (n = 30): UACR between 30-299 mg/gm and Macro-albuminuria Group (C) (n = 30): UACR equal or more than 300 mg/gm. Assess Urinary TNF-α and urine KIM-1 in comparision with albuminuria. Results Urinary KIM-1 and urinary TNF-α are statically significant with albuminuria in patients in the early stage of diabetic nephropathy (eGFR _60 mL/min/1.73 m2).Also there are statically significance between patients with macroalbuminuria than microalbuminuria. Conclusion The results of this study recommend the use of KIM-1 and TNF-α as good predictors of early detection of development of diabetic nephropathy.

scholarly journals A study of prevalence of microalbuminuria in recently detected type 2 diabetes and its relation to hypertension, dyslipidaemia and obesity

2020 ◽  
Vol 11 (5) ◽  
pp. 38-43
Author(s):  
Shrikrishna V Acharya
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Screening Tool ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Group 2 ◽  
Type 2 Diabetic ◽  
Group 1 ◽  
New Onset

Background: Microalbuminuria is one of the earliest markers of diabetic nephropathy, and if not recognized and treated early it may lead to diabetic nephropathy resulting in chronic renal failure. Aims and Objective: The aim of the current study was to find out the prevalence of microalbuminuria among newly detected Type 2 diabetic patients and also compare prevalence of microalbuminuria in patients with or without hypertension, dyslipidaemia and obesity. Materials and Methods: In this retrospective study, we analysed 90 patients with new onset type 2 diabetes mellitus. We divided the patients into two groups, group 1 with comorbidities like hypertension, dyslipidaemia and obesity (50 patients) and group 2 without comorbidities (40 patients). We analysed urinary microalbumin level in all patients and compared the prevalence of microalbuminuria between group 1 and group 2. Results: In our cohort of 90 patients, urinary microalbuminuria was found in 30 patients (33.3%). When we divided these nephropathy patients to group1 and group 2, we observed that group 1 with comorbidities had higher percentage of nephropathy patients i.e 24 out of 50(48%). Group 2 with 40 patients had only 6 patients with microalbiminuria ie 6 out of 40(15%). Incidence of microalbiminuria was higher in patients with hypertension, dyslipidaemia and obesity. Conclusions: We conclude that incidence of microalbiminuria is much more common in newly diagnosed type 2 diabetes. We also conclude that hypertension, obesity and hypercholesterolemia are risk factors for nephropathy and urinary microalbuminuria appears to be much more sensitive than serum creatinine as screening tool to detect diabetic nephropathy.

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