Transforming Growth Factor-β1/Smad Signaling in Glomerulonephritis and Its Association with Progression to Chronic Kidney Disease

2021 ◽  
Vol 52 (8) ◽  
pp. 653-665
Author(s):  
Aglaia Chalkia ◽  
Harikleia Gakiopoulou ◽  
Irini Theohari ◽  
Periklis G. Foukas ◽  
Dimitrios Vassilopoulos ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Risk Factor ◽  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Renal Inflammation ◽  
Smad Signaling ◽  
Interstitial Inflammation ◽  
Tgf Β1

<b><i>Introduction:</i></b> Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine, with diverse roles in fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-β/Smad signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). <b><i>Methods:</i></b> We evaluated the immunohistochemical expression of TGF-β1, phosphorylated Smad3 (pSmad3), and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN, and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression, and their role in progression to CKD. <b><i>Results:</i></b> TGF-β1 expression correlated positively with segmental glomerulosclerosis (<i>p</i><b></b>= 0.025) and creatinine level at diagnosis (<i>p</i> = 0.002), while pSmad3 expression with interstitial inflammation (<i>p</i> = 0.024). In glomerulus, concomitant expressions of high Smad7 and medium pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (<i>p</i> = 0.011), intense interstitial inflammation (<i>p</i> = 0.029), and lower serum complement (C) 3 (<i>p</i> = 0.028) and C4 (<i>p</i> = 0.029). We also reported a significant association between pSmad3 expression in glomerular endothelial cells of proliferative GN (<i>p</i> = 0.045) and in podocytes of nonproliferative GN (<i>p</i> = 0.005). Finally, on multivariate Cox-regression analysis, TGF-β1 expression (hazard ratio = 6.078; 95% confidence interval: 1.168–31.627; <i>p</i> = 0.032) was emerged as independent predictor for CKD. <b><i>Discussion/Conclusion:</i></b> TGF-β1/Smad signaling is upregulated with specific characteristics in different forms of GN. TGF-β1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.

scholarly journals Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Chenglei Zhao ◽  
Sean T. Zuckerman ◽  
Chuanqi Cai ◽  
Sreenivasulu Kilari ◽  
Avishek Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Arteriovenous Fistula ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Neointimal Hyperplasia ◽  
Systemic Delivery ◽  
Tgf Β1

Background Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end‐stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP‐SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease. Methods and Results Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 μL of PBS or 20 μL of PBS with 16.6 mg/mL of either MP or MP‐SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase–polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor‐A ( Vegf‐A ), matrix metalloproteinase‐9 ( Mmp‐9 ), transforming growth factor beta 1 ( Tgf‐β1 ), and monocyte chemoattractant protein‐1 ( Mcp‐1 ) were significantly decreased in MP‐SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP‐SV treated outflow veins. MP‐SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of Vegf‐A and Mmp‐9 . Conclusions In experimental arteriovenous fistulas, periadventitial delivery of MP‐SV decreased gene expression of Vegf‐A , Mmp‐9 , Tgf‐β1 and Mcp‐1, VNH/VS, inflammation, and fibrosis.

scholarly journals The Effect of Combination Therapy with Melatonin on the Enzymes of Glutathione System and the Level of Transforming Growth Factor- β1 in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease

2021 ◽  
Vol 11 (5) ◽  
pp. 359-369
Author(s):  
S. S. Popov ◽  
E. I. Anufrieva ◽  
E. D. Kryl’skii ◽  
A. N. Verevkin ◽  
K. K. Shulgin
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Lipid Profile ◽  
Antioxidant System ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Glutathione Antioxidant System

Aim. The aim of the work was to assess the effect of combination therapy with melatonin on the clinical and biochemical parameters of chronic kidney disease (CKD) and type 2 diabetes mellitus (DM), the level of transforming growth factor-β1, lipid profile, activity of the glutathione antioxidant system enzymes and the activity of NADPH-generating enzymes in patients.Materials and methods. The study involved 60 people (19 men and 41 women, average age 65.6 ± 9.3 years) with chronic kidney disease associated with type 2 diabetes. The patients were divided into 2 groups. The first group of patients received basic treatment (n = 30, 8 men and 22 women, mean age 64.1 ± 7.9 years); the second group of participants (n = 30, 11 men and 19 women, mean age 69.0 ± 10.5 years) received 2 mg of melatonin in addition to the basic therapy. The control group consisted of 65 apparently healthy individuals (30 men and 35 women, average age 42.3±17.7 years) with normal indicators of general and biochemical blood tests. In the course of the work, the analysis of clinical and biochemical indicators and lipid profile in blood serum, the level of transforming growth factor-β1 by enzyme immunoassay, the activity of enzymes of the glutathione antioxidant system and NADPH-generating enzymes by the spectrophotometric method were carried out.Results. The use of melatonin additionally with basic treatment compared with standard therapy led to a decrease in proteinuria (p=0.010), hyperglycemia (p=0.019), urea concentration (p=0.043), glycated hemoglobin (p=0.045) and transforming growth factor-β1 levels (p=0.020) in patients with CKD. In addition, the use of this drug led to a changing of the lipid profile, and the activity of glutathione antioxidant system enzymes and NADPH-generating enzymes.Conclusion. The differences observed during the study were apparently caused by the action of melatonin, which has nephroprotective and hypoglycemic properties, the ability to neutralize reactive oxygen species and activate the antioxidant system functioning. 

scholarly journals Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

2013 ◽  
Vol 305 (4) ◽  
pp. F477-F484 ◽  
Author(s):  
Sarah C. Huen ◽  
Gilbert W. Moeckel ◽  
Lloyd G. Cantley
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Transforming Growth Factor Β1 ◽  
Late Time ◽  
Tgf Β1

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

scholarly journals Mechanism of dietary salt-mediated increase in intravascular production of TGF-β1

2008 ◽  
Vol 295 (2) ◽  
pp. F406-F414 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Kristal Aaron ◽  
Paul W. Sanders
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Vascular Function ◽  
Transforming Growth Factor ◽  
Salt Intake ◽  
Dominant Negative ◽  
Dietary Salt ◽  
Tyrosine Kinase 2 ◽  
Tgf Β1

Clinical and preclinical studies have demonstrated an important effect of arterial pathobiology on the progressive loss of renal function that occurs in chronic kidney disease. Chronic kidney disease, in turn, promotes alterations in vascular function. A modulating role for dietary salt has been suggested, with the amount of salt intake regulating endothelial cell production of transforming growth factor-β1 (TGF-β1), a fibrogenic growth factor that promotes arteriosclerosis and glomerulosclerosis. The purpose of the present studies was to determine how the interaction between dietary salt intake and vasculature promoted the production of TGF-β1 in rats. Two different vascular tissues, aortic rings and glomeruli, were chosen for study. Dietary salt induced, in a dose-dependent fashion, activation of proline-rich tyrosine kinase-2 (Pyk2) and further identified c-Src as an important binding partner of Pyk2 in these tissues. Use of pharmacological inhibitors and dominant negative strategies confirmed that dietary salt induced complex formation of Pyk2 and c-Src with downstream activation of p38 and p42/44 mitogen-activated protein kinases and generation of TGF-β1. The experiments defined the molecular signaling events that promoted the production of TGF-β1, a key growth factor involved in the vascular response to increased salt intake.

scholarly journals Transforming Growth Factor-β1 as a Common Target Molecule for Development of Cardiovascular Diseases, Renal Insufficiency and Metabolic Syndrome

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ken-ichi Aihara ◽  
Yasumasa Ikeda ◽  
Shusuke Yagi ◽  
Masashi Akaike ◽  
Toshio Matsumoto
Keyword(s):  
Metabolic Syndrome ◽  
Chronic Kidney Disease ◽  
Cardiovascular Diseases ◽  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Coronary Intervention ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions

Transforming growth factor-β1 (TGF-β1) is a polypeptide member of the transforming growth factorβsuperfamily of cytokines. It is a secreted protein that performs many cellular functions including control of cell growth, cell proliferation, cell differentiation and apoptosis. In the cardiovascular system, TGF-β1 plays pivotal roles in the pathogenesis of hypertension, restenosis after percutaneous coronary intervention, atherosclerosis, cardiac hypertrophy and heart failure. In addition, TGF-β1 has been shown to be increased in adipose tissue of obese subjects with insulin resistance. Furthermore, TGF-β1 is a potent initiator of proliferation of renal mesangial cells leading to chronic kidney disease. Some currently available agents can manipulate TGF-β1 expression leading to amelioration of cardiovascular diseases. Thus, an understanding of interactions between chronic kidney disease and metabolic syndrome and the development of cardiovascular diseases is an important issue, and attention should be given to TGF-β1 as a crucial factor for regulation and modulation of those pathological conditions.

scholarly journals Evaluating the Serum Transforming Growth Factor-Beta 1 Level in Chronic Kidney Disease Caused by Glomerulonephritis

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Tuan Van Nguyen ◽  
Ky Duc Ngo ◽  
Minh Hoang Thi ◽  
Lan Thi Phuong Dam ◽  
Thuan Quang Huynh
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Healthy Control Group ◽  
Control Group ◽  
Healthy Control ◽  
Growth Factor Beta ◽  
Tgf Β1

Background: The transforming growth factor-beta 1 (TGF-β1) has been demonstrated as one of the main factors in the progression of fibrosis and sclerosis glomerular damages. Glomerulonephritis is one common cause of chronic kidney disease (CKD) with the promotion of inflammatory renal damage containing fibrosis and sclerosis glomerular. Objectives: This study aimed to evaluate the TGF-β1 level in CKD patients and compare it with the healthy control group. Methods: This cross-sectional case-control study was carried out on 212 subjects admitted to the Nghe An Friendship General Hospital in Vietnam from March 2018 to February 2020. The case group included 152 patients diagnosed with CKD caused by glomerulonephritis, and the control group included 60 healthy individuals. The TGF-β1 was determined in serum by ELISA method. Results: The serum TGF-β1 concentration of the healthy control group and CKD group was 13.45 ± 7.17 and 32.35 ± 11.74, respectively. The CKD group had a significantly higher TGF-β1 level than the control group (P < 0.05). The CKD group with the eGRP ≥ 60 mL/min/1.73 m2 group had a higher TGF-β1 level than the eGRP < 60 mL/min/1.73 m2 group, and the TGF-β1 level increased from stage 1 to stage 5 (P < 0.001). The TGF-β1 had a medium correlation to urea, creatinine, and hs-CRP. Conclusions: The concentration of TGF-β1 in the CKD group was higher than the control group so that it increased early from the first stage of the disease.

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