scholarly journals Angiotensin II and transforming growth factor β affect cardiovascular and renal disease in patients with type 2 diabetes mellitus: benefits of dpp-4 inhibitors treatment

2019 ◽  
Vol 16 (3) ◽  
pp. 55-61
Author(s):  
Teona A. Shvangiradze ◽  
Irina Z. Bondarenko ◽  
Ekaterina A. Troshina ◽  
Marina V. Shestakova ◽  
Larisa V. Nikankina ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Transforming Growth Factor ◽  
Kidney Damage ◽  
Ang Ii ◽  
Increased Risk ◽  
Wide Range

BACKGROUND: Diabetes mellitus type 2 (T2DM) is associated with impaired glucose metabolism and peripheral insulin resistance, which is accompanied by an high risk of cardiovascular disease (CVD) and nephropathy. Metabolic syndrome and T2DM are accompanied by renin-angiotensin system (RAS) activation, which is also associated with increased risk of CVD and kidney damage. Obesity lead to a wide range of pathophysiological changes, that stimulate cardiac fibrosis, and various fibrosis processes initiation, including activation of transforming growth factor (TGF-). AIMS: To determine activity of angiotensin II (Ang II) and TGF- in patients with obesity and T2DM and their association with heart and kidney damage. MATERIALS AND METHODS: Ang II and TGF- were identified in the peripheral blood of 66 obese patients aged 48-65 years. The first group included 21 patients with coronary heart disease (CHD) and T2DM; The second group included 22 patients with T2DM and excluded CHD; The third group 20 patients with normal glucose metabolism and excluded CHD. RESULTS: The values of TGF- in the 1st group (patients with CHD) were statistically lower than in the group of metabolically healthy obesity (p=0.021). Patients who received DPP-4 inhibitors had a lower Ang II level compared to patients with other hypoglycemic therapy (p=0.005). TGF- positively correlated with glomerular filtration rate (eGFR) in all patients (r=-0.414, p=0.006). TGF- negatively correlated with the degree of internal carotid artery stenosis in patients of the 2nd group (r=-0.42, p=0.09) and LDL-cholesterol in all patients (r=-0.426, p=0.038). CONCLUSIONS: TGF- negatively correlated with the factors that contribute to CVD progression. TGF- correlated with pathological angiogenesis and changes in normal cardiac geometry in obesity, T2DM and CHD. DPP-4 inhibitors can improve the cardiovascular prognosis in this group of patients by affecting Ang II level. Low levels of TGF- were associated with higher cardiovascular risk and were commonly found in patients with more severe nephropathy.

Clinical and pathogenetic features of intestinal lesions in patients with type 2 diabetes mellitus

2021 ◽  
Author(s):  
Y. Z. Dynia
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Growth Factor ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Clinical Manifestations ◽  
Intestinal Damage ◽  
Hydrogen Breath Test

Objective — to study the incidence and clinical and pathogenetic features of intestinal injury in patients with type 2 diabetes mellitus. Materials and methods. Examinations involved 138 patients with type 2 diabetes mellitus (DM 2), aged from 39 to 67 years (mean age 53 ± 5 years), including 82 women (59 %) and 56 men (41 %). In addition to general clinical methods, investigations included plasma levels of the transforming growth factor‑b1 (TGF‑b1) and vascular endothelial growth factor (VEGF), the hydrogen breath test with lactulose, endoscopic examination of the intestine with biopsy followed by staining with hematoxylin‑eosin, immunohistochemical determining of claudin‑1 and VEGF, and conduction of PAS‑reaction. Results. Diabetic enterocolopathy (DECP) was diagnosed in 72 (52.2 %) patients with DM 2. Clinical manifestations were nonspecific and similar to those of irritable bowel syndrome (IBS). It has been found that DECP correlates with the duration of the DM 2 course and was diagnosed more often in middle‑aged patients (52.1 ± 4.1 years). In patients with DECP, the increase in the proinflammatory cytokines TGF‑b1 and VEGF significantly exceeded those in IBS patients. Histologically the inflammatory cell infiltration in patients with DECP was more intense and diverse, there were signs of subatrophy of the glands with a relative decrease in the number of vacuoles in the goblet cells. The immunohistochemical study revealed that VEGF in the colon mucosa was visualized mainly in patients with DECP. Moreover, a tendency to a decrease in the claudin‑1 levels was established in these patients. Conclusions. Intestinal damage was revealed in 67.4 % of patients with type 2 diabetes mellitus, and DECP was diagnosed in more than half of patients. Diabetic enterocolopathy had nonspecific clinical symptoms, required differential diagnosis with IBS, and was not always accompanied with abdominal pain. The presence of DECP more often correlated with the bacterial overgrowth syndrome, and levels of proinflammatory cytokines in the blood plasma and intestinal mucosa of these patients was raised.  

Upregulation of α8β1-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-β1

2001 ◽  
Vol 281 (5) ◽  
pp. C1457-C1467 ◽  
Author(s):  
Gaétan Thibault ◽  
Marie-Josée Lacombe ◽  
Lynn M. Schnapp ◽  
Alexandre Lacasse ◽  
Fatiha Bouzeghrane ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Cardiac Fibroblast ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Tgf Β1

Using a novel pharmacological tool with125I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: α8β1, α3β1, α5β1, αvβ1, and αvβ3. Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-β1 (TGF-β1) resulted in an increase of protein and heightening by 50% of the receptor density of α8β1-integrin. The effect of ANG II was blocked by an AT1, but not an AT2, receptor antagonist, or by an anti-TGF-β1 antibody. ANG II and TGF-β1 increased fibronectin secretion, smooth muscle α-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The α8- and β1-subunits were colocalized by immunocytochemistry with vinculin or β3-integrin at focal adhesion sites. These results indicate that α8β1-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-β1 in a myofibroblast-like phenotype suggests the involvement of α8β1-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.

scholarly journals Evaluation of Transforming Growth Factor-Β1 Levels in Patients with Coronary Heart Disease in Combination with Type 2 Diabetes Mellitus

2021 ◽  
Vol 6 (1) ◽  
pp. 72-77
Author(s):  
R. F. Yeromenko ◽  
◽  
O. N. Litvinova ◽  
V. V. Kozar ◽  
A. L. Litvinenko ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Functional Classes

The purpose of the study was to examine the levels of transforming growth factor-β1 in the serum of patients with coronary heart disease in combination with type 2 diabetes and without it. Material and methods. We conducted a survey of 65 patients (25 men, 40 women) aged from 36 to 69 years (mean age was (59±3.5) years). All patients were diagnosed with coronary heart disease in the form of stable angina pectoris I-II functional classes. The group of examined patients included 33 patients with concomitant type 2 diabetes mellitus (mild form was in 15 people; moderate was in 18 people) and 32 patients without diabetes mellitus. The scope of the survey covered the generally accepted methods of clinical, laboratory and instrumental examination. The group of patients with coronary heart disease with type 2 diabetes had 14 (43%) men and 19 (57%) women (mean age was (62±2.6) years. Heart failure of stage I-II A (I-II functional classes) was diagnosed in 22 (68%) patients. The duration of coronary heart disease was from 3 to 15 years, the duration of type 2 diabetes lasted from 3 to 14. We detected hypertension in 19 (57%) patients, it was within 1-2 degrees (according to the criteria of the Ukrainian Association of Cardiologists, 2008). In the group of patients with coronary heart disease without diabetes there were 11 men (34%), 21 women (66%) (mean age was (57.0±2.4) years). Hypertension within 1-2 degrees was detected in 15 (46%) patients. Heart failure of I-II A stages (I-II functional classes) was diagnosed in 15 (46%) patients. The control group consisted of 15 practically healthy individuals who were representative by sex and age of patients from the study group and who did not have diseases of the cardiovascular system and endocrinopathies. The level of transforming growth factor-β1 in the blood serum was determined using sets of standard test systems "TGF-β1 ELISA" produced by company "DRG Instruments" (Germany). The level of native transforming growth factor-β1 in the serum was determined by solid-phase enzyme-linked immunosorbent assay. Results and discussion. Groups of patients with coronary heart disease with type 2 diabetes and without it could be compared by age, sex, duration and severity of coronary heart disease, the frequency of concomitant hypertension. At the same time, among patients with coronary heart disease with type 2 diabetes there was a higher frequency of heart failure. The results showed that probable increase in serum transforming growth factor-β1 levels in patients with coronary heart disease was more pronounced when combining coronary heart disease with type 2 diabetes. There was a significant increase in serum of transforming growth factor -β1 levels in patients with coronary heart disease both with type 2 diabetes and without it with a longer course of coronary heart disease and were severer, in patients with coronary heart disease with type 2 diabetes was with a longer course of diabetes. Analysis of the nature of changes in the levels of transforming growth factor-β1 in the serum of the examined patients with coronary heart disease with type 2 diabetes and without it, depending on gender, did not reveal any significant differences. The results of the study also indicated that in patients with coronary heart disease with type 2 diabetes and without it for all duration of coronary heart disease, the levels of this indicator in the serum were probably (p <0.05) higher than those in the control group. However, in patients with a significant duration of coronary heart disease (5-10 years and over 10 years) serum levels of transforming growth factor-β1 were probably (p <0.05) higher than in patients with a duration of coronary heart disease less than 5 years, and in the presence of and in the absence of type 2 diabetes. At the same time, for all periods of coronary heart disease, the levels of transforming growth factor-β1 in patients with type 2 diabetes were probably higher than in patients without diabetes. Conclusion. A probable increase in the levels of transforming growth factor -β1 in the serum of patients with coronary heart disease, which was more pronounced when combining coronary heart disease with type 2 diabetes. There was a significant increase in the levels of transforming growth factor-β1 in the serum of patients with coronary heart disease both with type 2 diabetes and without it with a longer course of coronary heart disease and its severe degree, in patients with coronary heart disease with type 2 diabetes especially with a longer course of diabetes. In order to increase the informativeness of assessing the risk of cardiovascular complications and the nature of coronary heart disease in patients with type 2 diabetes, the survey should include determination of serum levels of potent profibrogenic factor like transforming growth factor-β1

scholarly journals Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase

1997 ◽  
Vol 325 (2) ◽  
pp. 449-454 ◽  
Author(s):  
Katarina BEDECS ◽  
Nathalie ELBAZ ◽  
Malène SUTREN ◽  
Maryline MASSON ◽  
Christiane SUSINI ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinases ◽  
Tyrosine Phosphatase ◽  
At2 Receptor ◽  
Ang Ii ◽  
Mitogen Activated Protein ◽  
At2 Receptors

Angiotensin II type 2 (AT2) receptors are involved in the inhibition of cell proliferation as well as in apoptosis and neuronal differentiation, through intracellular signalling pathways that remain poorly defined. The present study examines the effect of AT2-receptor stimulation on growth-factor-induced pathways leading to the activation of mitogen-activated protein (MAP) kinases. In N1E-115 neuroblastoma cells, AT2 receptors inhibit the activity of MAP kinases induced by serum as well as by epidermal growth factor. The inhibitory effect of angiotensin II (Ang II) is rapid and transient, and affects both ERK1 and ERK2 (extracellular signal-related protein kinase) isoforms of the enzyme. AT2-mediated MAP kinase inactivation is not sensitive to pertussis toxin or okadaic acid, but involves a vanadate-sensitive protein tyrosine phosphatase (PTP). Expression of MAP kinase phosphatase-1 (MKP-1) is not significantly modified upon AT2-receptor activation, and insensitivity to actinomycin D also rules out transcriptional induction of other MKPs as a possible mechanism for AT2-mediated inactivation of MAP kinases. In addition, we report here that both in N1E-115 cells and in Chinese hamster ovary cells expressing recombinant human AT2 receptors, Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors. These findings thus demonstrate functional negative cross-talk between heptahelical AT2 receptors and receptor tyrosine kinases, and suggest that SHP-1 tyrosine phosphatase is an early transducer of the AT2 receptor signalling pathway.

scholarly journals The Role of Transforming Growth Factor-Beta in Diabetic Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Karina Braga Gomes ◽  
Kathryna Fontana Rodrigues ◽  
Ana Paula Fernandes
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Low Grade ◽  
Anti Inflammatory

Several studies have demonstrated that chronic and low-grade inflammation is closely linked to type 2 diabetes mellitus. The associated mechanisms are related to synthesis and release of proinflammatory and anti-inflammatory cytokines, mainly by the adipose tissue. Moreover, there are evidences that cytokines and adhesion molecules are important for development of diabetic nephropathy. Among the cytokines associated with inflammatory responses in type 2 diabetes mellitus, the transforming growth factor-β (TGF-β) has been recognized as a central player in the diabetic nephropathy being involved in the development of glomerulosclerosis and interstitial fibrosis, as observed in the course of end-stage renal disease. Although TGF-β1 is classically an anti-inflammatory immune mediator it has been shown that in the presence of IL-6, which increases before the onset of T2D, TGF-β1 favors the differentiation of T helper 17 (Th17) cells that are activated in many pro-inflammatory conditions. Since TGF-β1 mRNA and consequently serum TGF-β1 levels are under genetic control, this review aims to discuss the relationship of TGF-β1 levels and polymorphisms in the development of nephropathy in type 2 diabetes mellitus.

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