DNA double-strand breaks induced intractable glomerular fibrosis in renal allografts

Matsui, Yoshihiko; Sunatani, Yumi; Hayashi, Norifumi; Okino, Kazuaki; Okushi, Yuki; Mukai, Kiyotaka; Adachi, Hisashi; Yamaya, Hideki; Iwabuchi, Kuniyoshi; Yokoyama, Hitoshi

doi:10.1007/s10157-015-1174-3

Cited by 3 publications

(8 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a. γ-H2AX was detected in the nuclei of glomerular capillary cells, mainly endothelial cells, as previously reported 7 (Fig. 1a).…”

Section: Dna Damage Is Correlated With Col6 Deposition and Nodular Glsupporting

confidence: 87%

“…In a previous study, we demonstrated that the presence of DNA damage and COL6 deposition are positively correlated in the glomerulus of renal graft patients 7 . In this study, we examined this correlation in various kidney diseases, especially focusing on those with nodular glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 81%

“…Primary cell culture. HRGECs, which were described in a previous study 7 , were obtained from Scien-Cell Research Laboratories (PS-4000, San Diego, CA) and cultured following the manufacturer's instructions. Between 2 and 5 cell passages were used in these experiments.…”

Section: Biopsy Sample Collection and Pathological Evaluation A Totamentioning

confidence: 99%

“…Immunofluorescence. Fluorescence cell imaging procedures were performed as follows 7 . Cells were fixed with 4% paraformaldehyde at room temperature for 20 min, and were permeabilized with 0.1% Triton X-100/10% FBS/PBS for 1 h. To detect ANXA2, γ-H2AX, or COL6, cells were stained using a monoclonal mouse anti-human ANXA2 antibody (200 µg/mL, sc-28385, Santa Cruz Biotechnology, Dallas, TX) at a dilution of 1:50, a mouse monoclonal anti-human phospho-histone H2AX (Ser139) antibody at a dilution of 1:250, and a polyclonal rabbit anti-human COL6 antibody at a dilution of 1:2500, respectively.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Fujii

Sunatani

Furuichi

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Collagen 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.

show abstract

“…1a. γ-H2AX was detected in the nuclei of glomerular capillary cells, mainly endothelial cells, as previously reported 7 (Fig. 1a).…”

Section: Dna Damage Is Correlated With Col6 Deposition and Nodular Glsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 81%

Section: Biopsy Sample Collection and Pathological Evaluation A Totamentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Fujii

Sunatani

Furuichi

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…As well as diabetes nephropathy, FD nephropathy is proteinuric and has a metabolic origin and lyso‐Gb3 was proposed to be a fibrosis promoter in podocytes . Furthermore, DNA damage was recently linked to renal fibrosis and was also found increased in renal cells in a diabetes model …”

Section: Discussionmentioning

confidence: 99%

Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells

et al. 2017

View full text Add to dashboard Cite

Fabry disease (FD) is a lysosomal disorder caused by mutations leading to a deficient activity α-galactosidase A with progressive and systemic accumulation of its substrates. Substrates deposition is related to tissue damage in FD, but the underlying molecular mechanisms remain not completely understood. DNA damage has been associated with disease progression in chronic diseases and was recently described in high levels in Fabry patients. Once renal complications are major morbidity causes in FD, we investigated the effects of the latest biomarker for FD - globotriaosylsphingosine (lyso-Gb3) in a cultured renal lineage - human embryonic kidney cells (HEK-293 T) - on DNA damage. In concentrations found in Fabry patients, lyso-Gb3 induced DNA damage (by alkaline comet assay) with oxidative origin in purines and pyrimidines (by comet assay with endonucleases). These data provide new information about a deleterious effect of lyso-Gb3 and could be useful to studies looking for new therapeutic strategies to FD.

show abstract

Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys

Dragun¹,

Filipović

Racetin

et al. 2021

Applied Immunohistochemistry &Amp; Molecular Morphology

View full text Add to dashboard Cite

We studied the expression of mismatch repair genes (MMRs)-mutS protein homolog 2 (MSH2), PMS2, MutL homolog 1 (MLH1), and yH2AFX in diabetic rat kidneys. Streptozotocin-induced diabetes mellitus type 1 rat model (DM1) was used. Renal samples were collected 2 weeks and 2 months after DM1 induction and immunohistochemical expression of MMR genes in the renal cortex was analyzed. Diabetic animals showed lower MSH2 and higher yH2AFX kidney expression both 2 weeks and 2 months after DM1 induction. MLH1 expression significantly increased 2 weeks after DM1 induction (P < 0.0001). The most substantial differences were observed in the period 2 weeks after induction, with lower MSH2 and higher MLH1 expression in the proximal convoluted tubules and distal convoluted tubules (DCT) of diabetic animals (P < 0.001). yH2AFX expression significantly increased in the DCT of diabetic animals at both time points (P < 0.001; P < 0.01). PMS2 expression changed only in the glomeruli, where it significantly decreased 2 months after DM1 induction (P < 0.05). We concluded that the most substantial changes in renal expression of MMRs are happening already 2 weeks after diabetes induction, predominantly in the proximal convoluted tubules and DCT. Moreover, DCT could have a critical role in the pathophysiology of diabetic nephropathy (DN) and might be a future therapeutic target in this condition. The obtained results point to the MMRs as a potential factor in the development and progression of DN, as well as the possible link between DN and renal carcinogenesis.

show abstract

DNA double-strand breaks induced intractable glomerular fibrosis in renal allografts

Abstract: Our findings suggest that the long-term RT induces DSBs and HRGEc-secreted COL type VI accumulation in the glomerular capillaries, which might progress to intractable glomerular fibrosis.

Cited by 3 publications

References 29 publications

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

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

Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells

Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys

Contact Info

Product

Resources

About