scholarly journals Three-Dimensional Architecture of Glomerular Endothelial Cells Revealed by FIB-SEM Tomography

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuto Kawasaki ◽  
Yasue Hosoyamada ◽  
Takayuki Miyaki ◽  
Junji Yamaguchi ◽  
Soichiro Kakuta ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Three Dimensional ◽  
Surface Structures ◽  
Luminal Surface ◽  
Adult Rats ◽  
Glomerular Diseases ◽  
Subcellular Compartments ◽  
Glomerular Endothelial Cells ◽  
3D Architecture ◽  
Tubular Shape

Focused-ion beam-scanning electron microscopic (FIB-SEM) tomography enables easier acquisition of a series of ultrastructural, sectional images directly from resin-embedded biological samples. In this study, to clarify the three-dimensional (3D) architecture of glomerular endothelial cells (GEnCs) in adult rats, we manually extracted GEnCs from serial FIB-SEM images and reconstructed them on an Amira reconstruction software. The luminal and basal surface structures were clearly visualized in the reconstructed GEnCs, although only the luminal surface structures could be observed by conventional SEM. The luminal surface visualized via the reconstructed GEnCs was quite similar to that observed through conventional SEM, indicating that 3D reconstruction could be performed with high accuracy. Thus, we successfully described the 3D architecture of normal GEnCs in adult rats more clearly and precisely than ever before. The GEnCs were found to consist of three major subcellular compartments, namely, the cell body, cytoplasmic ridges, and sieve plates, in addition to two associated subcellular compartments, namely, the globular protrusions and reticular porous structures. Furthermore, most individual GEnCs made up a “seamless” tubular shape, and some of them formed an autocellular junction to make up a tubular shape. FIB-SEM tomography with reconstruction is a powerful approach to better understand the 3D architecture of GEnCs. Moreover, the morphological information revealed in this study will be valuable for the 3D pathologic evaluation of GEnCs in animal and human glomerular diseases and the structural analysis of developmental processes in the glomerular capillary system.

scholarly journals Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

2016 ◽  
Vol 40 (5) ◽  
pp. 819-830 ◽  
Author(s):  
Janina Müller-Deile ◽  
Finn Gellrich ◽  
Heiko Schenk ◽  
Patricia Schroder ◽  
Jenny Nyström ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Glomerular Filtration ◽  
Cell Types ◽  
Endothelial Damage ◽  
Micro Rna ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Glomerular Endothelial Cells ◽  
Apoptotic Pathways

Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

MO087PLASMALEMMAL VESICLE-ASSOCIATED PROTEIN-1 (PLVAP) INDICATES THE FORMATION OF DIAPHRAGM-BRIDGED FENESTRATIONS OF GLOMERULAR ENDOTHELIAL CELLS IN KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Björn Tampe ◽  
Laura Schridde ◽  
Samy Hakroush
Keyword(s):  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
Pore Formation ◽  
Major Protein ◽  
Glomerular Diseases ◽  
Glomerular Endothelial Cells ◽  
Peritubular Capillaries ◽  
Glomerular Endothelium ◽  
Fenestrated Endothelium ◽  
Glomerular Tuft

Abstract Background and Aims Plasmalemmal vesicle-associated protein-1 (PLVAP or PV-1) is a major protein of diaphragm-bridged fenestrated endothelial cells found in capillaries of neuroendocrine glands and peritubular capillaries. In contrast to peritubular capillaries, the glomerulus is known for its unique fenestrated endothelium without any diaphragm formation thereby ensuring free filtration. Here we aimed to investigate whether PLVAP is expressed in glomerular endothelial cells in various glomerular diseases and whether PLVAP expression is associated with the formation of diaphragm-bridged endothelial cells. Method A total number of 114 biopsy samples of glomerular diseases including diabetic nephropathy, FSGS, IgA-Nephritis, ANCA-GN and Lupus–Nephritis were analyzed immunohistochemistically for glomerular PLVAP expression. A fraction of PLVAP positive cases was subsequently investigated ultrastrucurally for the formation of diaphragm-bridged glomerular endothelial cells. Results One third of all cases showed at least one glomerulus with one single circumferential PLVAP staining. Interestingly, the most prominent staining, affecting the entire glomerular tuft, was observed in diabetic nephropathy and ANCA-GN. Ultrastructurally, such cases exhibited injured endothelium with focal detachment from the glomerular basement membrane, loss of pore formation and frequently diaphragm-bridged fenestrations reminiscent of peritubular capillaries. Conclusion Our data show that injured glomerular endothelium is capable of forming true diaphragm-bridged fenestrations, suggesting a possible role in preventing glomerular protein leakage and limiting its detachment from the GBM.

scholarly journals Manganese exposure induces permeability in renal glomerular endothelial cells via the Smad2/3-Snail–VE-cadherin axis

2020 ◽  
Vol 9 (5) ◽  
pp. 683-692
Author(s):  
Peng Gao ◽  
Yutian Tian ◽  
Qi Xie ◽  
Liang Zhang ◽  
Yongjian Yan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Zinc Finger Protein ◽  
Vascular Endothelial ◽  
Sprague Dawley ◽  
Glomerular Diseases ◽  
Cell Monolayers ◽  
Vascular Endothelial Cadherin ◽  
Glomerular Endothelial Cells ◽  
Sprague Dawley Rats ◽  
Glomerular Endothelium

Abstract Manganese (Mn) is an essential micronutrient. However, it is well established that Mn overexposure causes nervous system diseases. In contrast, there are few reports on the effects of Mn exposure on glomerular endothelium. In the present study, the potential effects of Mn exposure on glomerular endothelium were evaluated. Sprague Dawley rats were used as a model of Mn overexposure by intraperitoneal injection of MnCl2·H2O at 25 mg/kg body weight. Mn exposure decreased expression of vascular endothelial-cadherin, a key component of adherens junctions, and increased exudate from glomeruli in Sprague Dawley rats. Human renal glomerular endothelial cells were cultured with different concentration of Mn. Exposure to 0.2 mM Mn increased permeability of human renal glomerular endothelial cell monolayers and decreased vascular endothelial-cadherin expression without inducing cytotoxicity. In addition, Mn exposure increased phosphorylation of mothers against decapentaplegic homolog 2/3 and upregulated expression of zinc finger protein SNAI1, a negative transcriptional regulator of vascular endothelial-cadherin. Our data suggest Mn exposure may contribute to development of glomerular diseases by inducing permeability of glomerular endothelium.

scholarly journals Thrombin regulates PDGF expression in bovine glomerular endothelial cells.

1998 ◽  
Vol 9 (4) ◽  
pp. 583-589 ◽  
Author(s):  
G Grandaliano ◽  
G G Choudhury ◽  
E Poptic ◽  
K Woodruff ◽  
J L Barnes ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Glomerular Diseases ◽  
Cell Functions ◽  
Glomerular Endothelial Cells ◽  
Pathologic Features ◽  
A Chain

The proteolytic enzyme thrombin is produced during activation of the coagulation pathway. Intraglomerular fibrin deposition and thrombosis are common pathologic features of several glomerular diseases, including transplant rejection. The effect of thrombin on platelet-derived growth factor (PDGF) production and DNA synthesis in well characterized bovine glomerular endothelial cells (G/endo) was studied. DNA synthesis was measured as the amount of [3H]thymidine incorporated into acid-insoluble material. PDGF released in the supernatant was measured by Western blotting and by a radioreceptor assay. PDGF mRNA expression was analyzed by solution hybridization, using human genomic PDGF B-chain (c-sis) and A-chain cDNA probes. G/endo constitutively secrete PDGF activity in serum-free medium. Thrombin stimulates PDGF production and increases the expression of mRNA that hybridizes with labeled B-chain but not A-chain probe, whereas epidermal growth factor and transforming growth factor-alpha stimulate the expression of PDGF A-chain mRNA. In addition, thrombin stimulates DNA synthesis with a peak effect at 24 h. Unlike endothelial cells from other microvascular beds, G/endo did not respond to any of the three PDGF isoforms BB, AB, or AA. These data demonstrate that bovine G/endo produce PDGF and that thrombin stimulates de novo synthesis of PDGF from these cells. Because mesangial, but not bovine, G/endo express PDGF receptors, PDGF released by G/endo is likely to modulate mesangial cell functions such as proliferation and matrix production by means of a paracrine mechanism.

MO005GENERATION OF NOVEL 3D CO-CULTURE SYSTEMS TO STUDY PODOCYTOPATHIES EX VIVO IN A PERSONALIZED MANNER*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Victoria Rose ◽  
Nina Sopel ◽  
Alexandra Ohs ◽  
Christina Warnecke ◽  
Mario Schiffer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cell Lines ◽  
Ex Vivo ◽  
Time Lapse ◽  
Cell Types ◽  
Glomerular Diseases ◽  
Glomerular Cell ◽  
Glomerular Endothelial Cells ◽  
Culture Model

Abstract Background and Aims The smallest filtration unit of the kidney, the glomerulus, is composed of capillaries formed by glomerular endothelial cells (GEC), glomerular basement membrane and podocytes. Furthermore, glomerular mesangial cells (GMC) between the capillary loops give structural support. It is known that loss of podocyte foot processes is leading to a dysfunctional glomerular filtration barrier and is seen in glomerular diseases like focal segmental glomerulosclerosis and other podocytopathies. Indeed, it is hard to investigate podocytes in culture because podocytes are terminally end-differentiated cells that do not proliferate, lack foot processes and cell type-specific markers. Although conditionally immortalized human podocytes regained the capacity of proliferation, marker expression and behaviour differ between cell lines. The overarching aims of this study are to generate a 3D glomerular co-culture model that better reflects the in vivo phenotype of glomerular cell types. We want to investigate cell-cell contact, interaction and communication and extracellular matrix production in 3D glomerular co-cultures. Furthermore, patient-derived hiPSC-podocytes will be used in the glomerular co-cultures to investigate podocyte disease in a personalized manner and to identify potential therapeutic targets. Method The hanging droplet method was used to produce 3D glomerular spheroids. Therefore, human differentiated immortalized podocytes, human GECs and human GMCs were inserted in a medium-droplet hanging from the lid of a petri dish and harvested at different time points. Fluorescent cell lines of the different glomerular cell types were tracked in a time-lapse experiment to study if cell attachment and spheroid formation undergoes a specific order and structure. Glomerular spheroids were further characterized regarding the expression of podocyte-specific markers and extracellular matrix synthesis by immunohistochemistry, electron microscopy and qPCR and were compared to human cells isolated from glomeruli. Furthermore, scRNA-sequencing analysis was performed in 2D mono-cultures of human GECs, GMCs and immortalized podocytes and on 3D co-cultures to see if this change in culture conditions leads to transcriptomic alterations. For the generation of patient-derived podocytes, skin fibroblast of patients with podocyte mutations (INF2 mutation and WT1 mutation) and from healthy controls were reprogramed in iPSCs and differentiated into podocytes that keep the patient’s mutation. Results First time-lapse experiments of glomerular co-cultures showed that human podocytes and human glomerular endothelial cells attach to each other (Fig. 1a) and histological sections revealed that the glomerular spheroids are encapsulated by a monolayer of cells (Fig. 1b). SEM allowed ultrastructural characterization of the 3D spheroid-like structures (Fig. 1c). TEM revealed cell protrusions of podocytes that were not seen in monocultures (Fig. 1d, e). We could also demonstrate production of extracellular matrix by the cells (Fig. 1f). Immunohistochemistry and qPCR showed expression of collagen-IV and laminin. During the reprogramming of patient-derived fibroblasts, size of the generated hiPSC decreased and the nuclei to cell body ratio increased. HiPSCs formed colonies with distinct boarders and the proliferation rate increased. Furthermore, generated hiPSC showed similar gene expression of pluripotency markers compared to a commercial hiPSC control cell line and podocytes derived from these hiPSC expressed synaptopodin (Fig. 2). Conclusion We generated a 3D co-culture model that better represents the complexity of the glomerulus ex vivo. It is indicated that this model provides better physiological conditions. By an insertion of patient-specific hiPSC-derived podocytes in the 3D co-culture we will investigate glomerular diseases in a personalized manner in the future.

The significance of caveolae in the glomeruli in glomerular disease

2011 ◽  
Vol 64 (6) ◽  
pp. 504-509 ◽  
Author(s):  
Takahito Moriyama ◽  
Yuki Tsuruta ◽  
Ari Shimizu ◽  
Mitsuyo Itabashi ◽  
Takashi Takei ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Structural Characteristics ◽  
Basic Research ◽  
Recovery Phase ◽  
Clinical Findings ◽  
Glomerular Disease ◽  
Glomerular Diseases ◽  
Caveolin 1 ◽  
Glomerular Endothelial Cells ◽  
Main Component

AimsThe aim of this study was to demonstrate expression of cell membrane invagination ‘caveolae’ in glomeruli and to correlate this with functional and structural characteristics of the human glomerular diseases.MethodsThe expression of caveolin-1 (Cav-1), which is the main component of caveolae, was examined in the glomeruli, and the relationship between Cav-1 expression and pathological and clinical findings was determined in 99 patients with glomerular disease and in 50 renal transplantation donors as controls.ResultsCav-1 was expressed very weakly in the controls, and the area of Cav-1 expression relative to the total glomerular area was 0.57±0.65%. However, the area of Cav-1 expression was significantly larger in each glomerular disease (IgA nephropathy, 1.05±1.36%, p<0.05; crescent glomerulonephritis, 1.86±1.19%, p<0.001; minimal change disease, 2.38±1.24%, p<0.001; focal segmental glomerulosclerosis, 2.88±2.05%, p<0.01; membranous nephritis, 4.27±2.95%, p<0.001; membranoproliferative glomerulonephritis, 4.49±3.15%, p<0.001; and diabetic nephropathy, 2.45±1.52%, p<0.001; compared with the controls. Cav-1 expression was significantly decreased in glomerular disease treated with steroids. Co-localisation of Cav-1 and the endothelial marker ‘pathologische anatomie leiden-endothelium’ was prominent in an immunofluorescence study, and caveolae on the glomerular endothelial cells were observed in electron microscopy.ConclusionsThe expression of Cav-1 was significantly increased in the glomeruli of patients with glomerular disease, and it was related to urinary albumin excretion. Cav-1 expression and caveolae were observed in glomerular endothelial cells. It is hypothesised that they play a role in the recovery phase of capillary injury or endocytosis of albumin into endothelial cells. Basic research should be performed to elucidate the role played by Cav-1 and caveolae.

scholarly journals DNA damage in human glomerular endothelial cells induces nodular glomerulosclerosis via an ATR and ANXA2 pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ai Fujii ◽  
Yumi Sunatani ◽  
Kengo Furuichi ◽  
Keiji Fujimoto ◽  
Hiroki Adachi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Endothelial Cells ◽  
Specific Inhibitor ◽  
Glomerular Diseases ◽  
Histone H2ax ◽  
Nodular Glomerulosclerosis ◽  
Glomerular Endothelial Cells ◽  
Human Glomerular Endothelial Cells ◽  
Nodular Lesions

AbstractCollagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (β: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.

scholarly journals TGF-β1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sayo Ueda ◽  
Tatsuya Tominaga ◽  
Arisa Ochi ◽  
Akiko Sakurai ◽  
Kenji Nishimura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Senescence ◽  
Nuclear Translocation ◽  
Kidney Diseases ◽  
The Novel ◽  
Glomerular Diseases ◽  
Cycle Arrest ◽  
Glomerular Endothelial Cells ◽  
Tgf Β1

Abstractp16 inhibits cyclin-dependent kinases and regulates senescence-mediated arrest as well as p21. Nuclear p16 promotes G1 cell cycle arrest and cellular senescence. In various glomerular diseases, nuclear p16 expression is associated with disease progression. Therefore, the location of p16 is important. However, the mechanism of p16 trafficking between the nucleus and cytoplasm is yet to be fully investigated. TGF-β1, a major cytokine involved in the development of kidney diseases, can upregulate p21 expression. However, the relationship between TGF-β1 and p16 is poorly understood. Here, we report the role of podocyte TGF-β1 in regulating the p16 behavior in glomerular endothelial cells. We analyzed podocyte-specific TGF-β1 overexpression mice. Although p16 was found in the nuclei of glomerular endothelial cells and led to endothelial cellular senescence, the expression of p16 did not increase in glomeruli. In cultured endothelial cells, TGF-β1 induced nuclear translocation of p16 without increasing its expression. Among human glomerular diseases, p16 was detected in the nuclei of glomerular endothelial cells. In summary, we demonstrated the novel role of podocyte TGF-β1 in managing p16 behavior and cellular senescence in glomeruli, which has clinical relevance for the progression of human glomerular diseases.

scholarly journals Enzymatic processing of angiotensin peptides by human glomerular endothelial cells

2012 ◽  
Vol 302 (12) ◽  
pp. F1583-F1594 ◽  
Author(s):  
Juan Carlos Q. Velez ◽  
Jessalyn L. Ierardi ◽  
Alison M. Bland ◽  
Thomas A. Morinelli ◽  
John M. Arthur ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Messenger Rna ◽  
Cell Types ◽  
Specific Cell ◽  
Ang Ii ◽  
Glomerular Diseases ◽  
Glomerular Cell ◽  
Glomerular Endothelial Cells ◽  
Neprilysin Inhibitor ◽  
Aspartyl Aminopeptidase

The intraglomerular renin-angiotensin system (RAS) is linked to the pathogenesis of progressive glomerular diseases. Glomerular podocytes and mesangial cells play distinct roles in the metabolism of angiotensin (ANG) peptides. However, our understanding of the RAS enzymatic capacity of glomerular endothelial cells (GEnCs) remains incomplete. We explored the mechanisms of endogenous cleavage of ANG substrates in cultured human GEnCs (hGEnCs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and isotope-labeled peptide quantification. Overall, hGEnCs metabolized ANG II at a significantly slower rate compared with podocytes, whereas the ANG I processing rate was comparable between glomerular cell types. ANG II was the most abundant fragment of ANG I, with lesser amount of ANG-(1–7) detected. Formation of ANG II from ANG I was largely abolished by an ANG-converting enzyme (ACE) inhibitor, whereas ANG-(1–7) formation was decreased by a prolylendopeptidase (PEP) inhibitor, but not by a neprilysin inhibitor. Cleavage of ANG II resulted in partial conversion to ANG-(1–7), a process that was attenuated by an ACE2 inhibitor, as well as by an inhibitor of PEP and prolylcarboxypeptidase. Further fragmentation of ANG-(1–7) to ANG-(1–5) was mediated by ACE. In addition, evidence of aminopeptidase N activity (APN) was demonstrated by detecting amelioration of conversion of ANG III to ANG IV by an APN inhibitor. While we failed to find expression or activity of aminopeptidase A, a modest activity attributable to aspartyl aminopeptidase was detected. Messenger RNA and gene expression of the implicated enzymes were confirmed. These results indicate that hGEnCs possess prominent ACE activity, but modest ANG II-metabolizing activity compared with that of podocytes. PEP, ACE2, prolylcarboxypeptidase, APN, and aspartyl aminopeptidase are also enzymes contained in hGEnCs that participate in membrane-bound ANG peptide cleavage. Injury to specific cell types within the glomeruli may alter the intrarenal RAS balance.

scholarly journals TGF-β1 is Involved in Senescence-Related Pathways in Glomerular Endothelial Cells by p16 Translocation and p21 Induction.

2021 ◽  
Author(s):  
Sayo Ueda ◽  
Tatsuya Tominaga ◽  
Arisa Ochi ◽  
Akiko Sakurai ◽  
Kenji Nishimura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Senescence ◽  
Nuclear Translocation ◽  
Kidney Diseases ◽  
Human Kidney ◽  
Glomerular Diseases ◽  
Glomerular Endothelial Cells ◽  
Developing Kidney ◽  
Tgf Β1

Abstract p16 is an inhibitor of cyclin-dependent kinases and regulating senescence-mediated arrest as well as p21. The expression of p16 has been evaluated in human kidney diseases. However, the regulation of p16 nuclear translocation has yet to be fully investigated. TGF-β1 is well-known to be one of the major cytokines in developing kidney diseases. TGF-β1 can upregulate p21 expression and be involved in the process of senescence. In contrast, the relationship between TGF-β1 and p16 has been poorly investigated. Here, we report the role of TGF-β1-Smad3 pathway to regulate the p16 behavior in glomerular endothelial cells. To clarify the role of TGF-β1 in the regulation of p16, we analyzed podocyte-specific TGF-β1 overexpression mice. In glomeruli, p16 was found in the nuclei of glomerular endothelial cells, leading to endothelial cellular senescence. However, the expression level of p16 was not increased in glomeruli. In cultured endothelial cells, TGF-β1 induced nuclear translocation of p16 without the increase in p16 expression. Among human glomerular diseases, p16 was detected in the nuclei of endothelial cells. In summary, we could show the novel role of podocyte TGF-β1 in the management of p16 behavior and cellular senescence in glomeruli, which has clinical relevance for human glomerular diseases.

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