Participation of bone morphogenetic protein (BMP)-6 and osteopontin in cisplatin (CDDP)-induced rat renal fibrosis

Yano, Ryo; Golbar, Hossain M.; Izawa, Takeshi; Sawamoto, Osamu; Kuwamura, Mitsuru; Yamate, Jyoji

doi:10.1016/j.etp.2014.10.002

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…In CDDP-induced rat renal fibrosis, NGAL expression was seen in completely regenerating proximal renal tubules with regularly arranged epithelial cells, correlating well with proliferating activity. Interestingly, OPN expression was seen in dilated or atrophied abnormal renal tubules surrounded by flattened or irregularly-arranged epithelia, around which interstitial fibrosis was taking place; the increased expression of OPN significantly correlated with α-SMA-positive myofibroblast appearance, expression of TGF-β1 mRNA and CD68-positive macrophages [ 79 , 80 ]. Treatment of NRK-52E with TGF-β1 decreased NGAL expression, whereas OPN expression was increased; furthermore, E -cadherin was decreased but α-SMA expression was increased.…”

Section: Pathogenesis Of Type 2 Epithelial To Mesenchymal Transitimentioning

confidence: 99%

“…Similarly, BMP-6 deficiency aggravate interstitial damage and fibrosis in UUO mouse model independent of BMP-7 [ 92 ]. In CDDP-induced rat renal fibrosis, BMP-6 expression was seen in abnormal renal epithelial cells and also in peri-tubular myofibroblasts in CDDP-induced rat renal fibrosis [ 80 ]. The addition of TGF-β1 to NRK-52E increased expression of BMP-6; on the contrary, BMP-6 treatment decreased TGF-β1 expression of NRK-52E cells.…”

Section: Pathogenesis Of Type 2 Epithelial To Mesenchymal Transitimentioning

confidence: 99%

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Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Tennakoon

Izawa

Kuwamura

et al. 2015

JCM

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Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data.

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Section: Pathogenesis Of Type 2 Epithelial To Mesenchymal Transitimentioning

confidence: 99%

Section: Pathogenesis Of Type 2 Epithelial To Mesenchymal Transitimentioning

confidence: 99%

Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Tennakoon

Izawa

Kuwamura

et al. 2015

JCM

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“…BMP6 is involved in the pathophysiology of chronic heart failure (30). Increasing BMP6 expression, induced by TGF activation, promotes tissue fibrosis and new vascular development, as well as inhibiting cell proliferation (22,31,32). The decreased cell viability and increased apoptosis observed in the present study may in part be due to the activation of the TGF-β-BMP signaling pathway, which may be a target for treating cardiac amyloidosis.…”

Section: Discussionmentioning

confidence: 71%

Analysis of gene expression profiling of amyloidogenic immunoglobulin light‑chains on cultured rat cardiomyocytes

Wang

et al. 2020

Exp Ther Med

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The present study aimed to investigate the toxic effects of different amyloidogenic light-chains (LCs) on cardiomyocytes, and demonstrate the differentially expressed genes (DEGs) and signaling pathways that participate in this process. Cultured cardiomyocytes were treated with recombinant κ LC peptide (AL-09) or with serum from a patient diagnosed with multiple myeloma (λ LC) with cardiac involvement. The 6xHis peptide or serum from healthy patients was used as peptide control or serum control, respectively. Cell viability was determined using CCK-8 assay and apoptosis was analyzed by flow cytometry. The DEGs were detected by RNA sequencing (RNA-Seq), followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Changes in gene expression levels were confirmed by reverse transcription-quantitative PCR. The cell viability in the AL-09 peptide-treated (0.2 mg/ml) and patient serum-treated (1:10 dilution) cardiomyocytes decreased to 42 and-72% of the corresponding control groups. The extent of cell apoptosis increased in AL-09-treated cardiomyocytes compared with the control group. RNA-Seq showed 256 DEGs co-existed in the two paired groups, including 127 upregulated and 88 downregulated genes. The KEGG pathways for upregulated expressed genes included the 'TGF-β signaling pathway', the 'Hedgehog signaling pathway', the 'ErbB signaling pathway' and 'lysine degradation'. The higher mRNA expression of bone morphogenetic protein (Bmp) 4, Bmp6, prostaglandin G/H synthase (Ptgs)1, Ptgs2, epiregulin, Tgfa and procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 were confirmed. The KEGG pathways of downregulated expressed genes included genes involved with the 'p53 signaling pathway' and the 'cell cycle'. The mRNA expression levels of E3 ubiquitin-protein ligase CCNB1IP1 showed significant downregulation in the AL-09 peptide group compared with those in the 6xHis peptide group. In conclusion, cardiomyocytes treated with amyloidogenic λ and κ LCs presented with decreased cell viability compared with controls. Cell apoptosis increased in κ LC-treated cells compared with controls. The gene expression profiles associated with transforming growth factor-β-bone morphogenetic protein, the receptor tyrosine-protein kinase erbB-2 signaling pathways, prostaglandins, collagen production, the p53 signaling pathway and the cell cycle were altered in light-chain-treated cardiomyocytes.

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“…18 In OPN knockout mice, monocyte/macrophage infiltration is significantly reduced, and the tubular interstitial fibrosis is dramatically inhibited. 19 The mechanisms of OPN-induced renal fibrosis include: [18][19][20][21][22] first, as a powerful macrophage chemokine, OPN promotes macrophage gathering in the renal interstitial region and binds to OPN receptors on the cell surface of macrophages, which induces the release of TGF-b1, platelet-derived growth factor (PDGF), IL-1, and other cytokines. It can also…”

Section: Discussionmentioning

confidence: 99%

Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

Zhang

et al. 2015

Renal Failure

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Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5 mg/kg) and high dose (10 mg/kg) of leflunomide, and benazepril hydrochloride (4 mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p50.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-b1), a-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-b1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelialmyofibroblast transdifferentiation.

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Participation of bone morphogenetic protein (BMP)-6 and osteopontin in cisplatin (CDDP)-induced rat renal fibrosis

Cited by 14 publications

References 25 publications

Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Analysis of gene expression profiling of amyloidogenic immunoglobulin light‑chains on cultured rat cardiomyocytes

Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

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