Pathological changes, TGF-<b>β</b>1 expression, and the effects of hepatocyte growth factor in 5/6 nephrectomized rats

Wang, Hongyue; Yang, Lizhi; Gu, Chunmei; Chen, Yan; Zhao, Ying; Zhao, Dan; Li, Tianshu; Ming-ji, Cui

doi:10.3109/0886022x.2013.867797

Cited by 5 publications

(5 citation statements)

References 22 publications

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“…At present, the majority of studies have focused on the early stage of chronic renal failure (5 weeks after 5/6 Nx). The protective role of lotensin during early chronic renal failure has been well-investigated [16]. However, it remains unknown whether lotensin also protects against late-stage chronic renal failure.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of transforming growth factor-β1 and α-smooth muscle actin contributes to the protection of lotensin against chronic renal failure in rats

Xiao

Guan

et al. 2018

Renal Failure

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Background: Lotensin has been shown to have a protective function in the early stage of chronic renal failure. However, its role in the intermediate and late stages of chronic renal failure remains largely unknown. The present study aimed to investigate the role and underlying mechanism of lotensin in advanced chronic kidney disease.Methods: Female Wistar rats were randomly divided into three groups (n = 10): sham group, 5/6 nephrectomy (5/6 Nx) group, and lotensin group (oral administration of lotensin for 9 weeks following 5/6 Nx). Rats were sacrificed and pathological parameters were measured. Western blot assay and immunohistochemical staining were performed to detect the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in kidney tissues.Results: Compared to the 5/6 Nx group, lotensin administration significantly decreased 5/6 Nx-induced elevation in blood urea nitrogen, serum creatinine and 24-h urinary protein excretion (UPE) rates, but markedly increased red blood cell count, plasma albumin and hemoglobin levels, along with improved renal morphology. Mechanistically, lotensin dramatically downregulated the renal expression of TGF-β1 and α-SMA induced by 5/6 Nx.Conclusions: Lotensin protects against advanced chronic kidney disease in rats with 5/6 Nx through the downregulation of TGF-β1 and α-SMA.

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Section: Discussionmentioning

confidence: 99%

Decreased expression of transforming growth factor-β1 and α-smooth muscle actin contributes to the protection of lotensin against chronic renal failure in rats

Xiao

Guan

et al. 2018

Renal Failure

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“…The discrepancy of our data with reports of TGF-β1 overexpression models [ 3 , 46 , 47 ], which demonstrate proteinuria and podocyte apoptotic changes, may be due to differences in timing and levels of TGF-β expression, or in the mode of podocyte damage. Indeed, upregulation of TGF-β is preceded by onset of proteinuria in many models [ 20 , 53 ]. Further, plasma TGF-β levels reported in human patients are approximately 10–50 ng/ml [ 13 , 54 ], which is much lower than that achieved in TGF-β-overexpressing mice (10–30 mg/ml) [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-TGF-β Antibody, 1D11, Ameliorates Glomerular Fibrosis in Mouse Models after the Onset of Proteinuria

et al. 2016

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Fibrosis is a final common pathway leading to loss of kidney function, in which the fibrogenic cytokine, transforming growth factor β (TGF-β), plays a central role. While previous studies showed that TGF-β antagonism by various means prevents fibrosis in mouse models, clinical approaches based on these findings remain elusive. 1D11 is a neutralizing antibody to all three isoforms of TGF-β. In both adriamycin (ADR)-induced nephropathy and NEP25 podocyte ablation nephropathy, thrice-weekly intraperitoneal administration of 1D11 from the day of disease induction until the mice were sacrificed (day 14 for ADR and day 28 for NEP25), significantly reduced glomerular COL1A2 mRNA accumulation and histological changes. Consistent with our previous findings, proteinuria remained overt in the mice treated with 1D11, suggesting distinct mechanisms for proteinuria and fibrogenesis. Podocyte numbers determined by WT1 staining were significantly reduced in NEP25-model glomeruli as expected, while WT1-positive cells were preserved in mice receiving 1D11. Even when 1D11 was administered after the onset of proteinuria on day 3, 1D11 preserved WT1-positive cell numbers in glomeruli and significantly reduced glomerular scar score (2.5 ± 0.2 [control IgG] vs. 1.8 ± 0.2 [1D11], P < 0.05) and glomerular COL1A2 mRNA expression (19.3 ± 4.4 [control IgG] vs. 8.4 ± 2.4 [1D11] fold increase over the healthy control, P < 0.05). Transmission electron microscopy revealed loss of podocytes and denuded glomerular basement membrane in NEP25 mice with disease, whereas podocytes remained attached to the basement membrane, though effaced and swollen, in those receiving 1D11 from day 3. Together, these data suggest that TGF-β neutralization by 1D11 prevents glomerular fibrosis even when started after the onset of proteinuria. While overt proteinuria and podocyte effacement persist, 1D11 prevents total podocytes detachment, which might be a key event activating fibrogenic events in glomeruli.

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“…Consistent with the previous report, the exosomes also exert an anti-fibrotic role in the 5/6 nephrectomy rat, for reducing the fibrotic area as well as the fibrotic markers. In the nephrectomy rats, TGF-β1 plays a crucial role in triggering renal fibrogenesis by breaking the balance of ECM synthesis/degradation [23]. TGF-β1 also promotes renal tubular epithelial cells emerging a fibrotic phenotype thus accelerate the process of renal fibrosis [24].…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis via regulating Smurf 2/Smad 7

Liu¹,

Wei²,

Yan³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Exosomes can be secreted from bone marrow mesenchymal stem cells (BMSCs) to extracellular space and exert antifibrotic effects, but the underlying mechanisms remain to be elucidated. Methods: 5/6 subtotal nephrotomy (SNx) rat models and TGF-β1-induced human renal proximal tubular epithelial cells (HRPTEpiCs) were established to simulate renal fibrosis. Renal function and fibrosis were assessed by Hematoxylin and Eeosin (HE) staining, Masson staining, immunohistochemistry, and western blot. The expression of Smad 7/Smurf 2 was detected in rats and HRPTEpiCs by western blot, and a further potential mechanism was explored using si-Smurf 2. Results: BMSC-Exo improved renal function, reduced the fibrotic region, down-regulated the expression of fibronectin, Collagen-I, α-SMA, and up-regulated E-cadherin in SNx models. In vitro study demonstrated that knocking down the expression of Smurf 2 significantly increased the expression of Smad 7, which could be enhanced by BMSC-Exo. BMSC-Exo could alleviate the fibrosis induced by TGF-β1 in tubular epithelial cells and enhanced the protective effect of si-Smurf 2 on renal fibrosis. Conclusions: BMSC-Exo inhibited renal fibrosis both in vivo and in vitro, partially, by regulating the Smurf 2/Smad 7 axis. BMSC-Exo enhanced the protective effect of si-Smurf 2 on fibrosis induced by transforming growth factor-β1 (TGF-β1).

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Pathological changes, TGF-β1 expression, and the effects of hepatocyte growth factor in 5/6 nephrectomized rats

Cited by 5 publications

References 22 publications

Decreased expression of transforming growth factor-β1 and α-smooth muscle actin contributes to the protection of lotensin against chronic renal failure in rats

Decreased expression of transforming growth factor-β1 and α-smooth muscle actin contributes to the protection of lotensin against chronic renal failure in rats

Anti-TGF-β Antibody, 1D11, Ameliorates Glomerular Fibrosis in Mouse Models after the Onset of Proteinuria

Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis via regulating Smurf 2/Smad 7

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