Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes

2013 ◽  
Vol 305 (9) ◽  
pp. F1249-F1264 ◽  
Author(s):  
Magdalena Mazagova ◽  
Hendrik Buikema ◽  
Azuwerus van Buiten ◽  
Marry Duin ◽  
Maaike Goris ◽  
...  
Keyword(s):  
Renal Damage ◽  
Tissue Injury ◽  
Tubular Damage ◽  
Diabetic Kidney ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Genetic Deletion ◽  
Glomerular Damage

Growth differentiation factor 15 (GDF15) is emerging as valuable biomarker in cardiovascular disease and diabetic kidney disease. Also, GDF15 represents an early response gene induced after tissue injury and studies performed in GDF15 knockout (KO) mice suggest that GDF15 plays a protective role after injury. In the current study, we investigated the role of GDF15 in the development of diabetic kidney damage in type 1 and type 2 models of diabetes. Renal damage was assessed in GDF15 KO mice and wild-type (WT) mice in streptozotocin type 1 and db/db type 2 diabetic models. Genetic deletion of GDF15 augmented tubular and interstitial damage in both models of diabetes, despite similar diabetic states in KO and WT mice. Increased tubular damage in KO animals was associated with increased glucosuria and polyuria in both type 1 and type 2 models of diabetes. In both models of diabetes, KO mice showed increased interstitial damage as indicated by increased α-smooth muscle actin staining and collagen type 1 expression. In contrast, glomerular damage was similarly elevated in diabetic KO and WT mice. In type 1 diabetes, GDF15 KO mice demonstrated increased expression of inflammatory markers. In type 2 diabetes, elevated levels of plasma creatinine indicated impaired kidney function in KO mice. GDF15 protects the renal interstitium and tubular compartment in experimental type 1 and 2 diabetes without affecting glomerular damage.

scholarly journals Progression of diabetic kidney disease in T2DN rats

2019 ◽  
Vol 317 (6) ◽  
pp. F1450-F1461 ◽  
Author(s):  
Oleg Palygin ◽  
Denisha Spires ◽  
Vladislav Levchenko ◽  
Ruslan Bohovyk ◽  
Mykhailo Fedoriuk ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Renal Damage ◽  
Diabetic Kidney Disease ◽  
Weight Ratio ◽  
Renin Angiotensin Aldosterone System ◽  
Diabetic Kidney ◽  
Renin Angiotensin ◽  
Glomerular Damage

Diabetic kidney disease (DKD) is one of the leading pathological causes of decreased renal function and progression to end-stage kidney failure. To explore and characterize age-related changes in DKD and associated glomerular damage, we used a rat model of type 2 diabetic nephropathy (T2DN) at 12 wk and older than 48 wk. We compared their disease progression with control nondiabetic Wistar and diabetic Goto-Kakizaki (GK) rats. During the early stages of DKD, T2DN and GK animals revealed significant increases in blood glucose and kidney-to-body weight ratio. Both diabetic groups had significantly altered renin-angiotensin-aldosterone system function. Thereafter, during the later stages of disease progression, T2DN rats demonstrated a remarkable increase in renal damage compared with GK and Wistar rats, as indicated by renal hypertrophy, polyuria accompanied by a decrease in urine osmolarity, high cholesterol, a significant prevalence of medullary protein casts, and severe forms of glomerular injury. Urinary nephrin shedding indicated loss of the glomerular slit diaphragm, which also correlates with the dramatic elevation in albuminuria and loss of podocin staining in aged T2DN rats. Furthermore, we used scanning ion microscopy topographical analyses to detect and quantify the pathological remodeling in podocyte foot projections of isolated glomeruli from T2DN animals. In summary, T2DN rats developed renal and physiological abnormalities similar to clinical observations in human patients with DKD, including progressive glomerular damage and a significant decrease in renin-angiotensin-aldosterone system plasma levels, indicating these rats are an excellent model for studying the progression of renal damage in type 2 DKD.

scholarly journals Growth differentiation factor 15 and early prognosis after out-of-hospital cardiac arrest

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ferran Rueda ◽  
Germán Cediel ◽  
Cosme García-García ◽  
Júlia Aranyó ◽  
Marta González-Lopera ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Tissue Injury ◽  
Cerebral Performance Category ◽  
Neurologic Outcome ◽  
Home Setting ◽  
Growth Differentiation Factor 15 ◽  
Poor Outcome ◽  
Differentiation Factor ◽  
Hospital Cardiac Arrest ◽  
Early Predictor

Abstract Background Growth differentiation factor 15 (GDF-15) is an inflammatory cytokine released in response to tissue injury. It has prognostic value in cardiovascular diseases and other acute and chronic conditions. Here, we explored the value of GDF-15 as an early predictor of neurologic outcome after an out-of-hospital cardiac arrest (OHCA). Methods Prospective registry study of patients in coma after an OHCA, admitted in the intensive cardiac care unit from a single university center. Serum levels of GDF-15 were measured on admission. Neurologic status was evaluated according to the cerebral performance category (CPC) scale. The relationship between GDF-15 levels and poor neurologic outcome at 6 months was analyzed. Results Among 62 patients included, 32 (51.6%) presented poor outcome (CPC 3–5). Patients with CPC 3–5 exhibited significantly higher GDF-15 levels (median, 17.1 [IQR, 11.1–20.4] ng/mL) compared to those with CPC 1–2 (7.6 [IQR, 4.1–13.1] ng/mL; p = 0.004). Multivariable logistic regression analyses showed that age (OR, 1.09; 95% CI 1.01–1.17; p = 0.020), home setting arrest (OR, 8.07; 95% CI 1.61–40.42; p = 0.011), no bystander cardiopulmonary resuscitation (OR, 7.91; 95% CI 1.84–34.01; p = 0.005), and GDF-15 levels (OR, 3.74; 95% CI 1.32–10.60; p = 0.013) were independent predictors of poor outcome. The addition of GDF-15 in a dichotomous manner (≥ 10.8 vs. < 10.8 ng/mL) to the resulting clinical model improved discrimination; it increased the area under the curve from 0.867 to 0.917, and the associated continuous net reclassification improvement was 0.90 (95% CI 0.48–1.44), which allowed reclassification of 37.1% of patients. Conclusions After an OHCA, increased GDF-15 levels were an independent, early predictor of poor neurologic outcome. Furthermore, when added to the most common clinical factors, GDF-15 improved discrimination and allowed patient reclassification.

scholarly journals Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

2018 ◽  
Vol 5 (7) ◽  
pp. 2480-2492
Author(s):  
Alexander E. Berezin ◽  
Alexander A. Kremzer ◽  
Daniel Petrovich ◽  
Ioana Mozos ◽  
Alexander A. Berezin
Keyword(s):  
Logistic Regression ◽  
Healthy Volunteers ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Endothelial Progenitor ◽  
Growth Differentiation Factor 15 ◽  
Type 2 Dm ◽  
Differentiation Factor ◽  
Hs Crp

The objective: to investigate the relationship between levels of growth differentiation factor-15 (GDF-15) and circulating number of endothelial progenitor cells (EPCs) with angiopoietin phenotypes: CD34+CD14+CD309+, and CD34+CD14+CD309+Tie2+ in patients with type 2 DM. Methods: The study was retrospectively involved 76 patients with type 2 DM aged 38 to 55 years and 30 healthy volunteers. Data collection included demographic and anthropometric information, hemodynamic performances and biomarkers of the diseases. Flow cytometry was used to determine EPCs' populations. Results: The levels of GDF-15 in peripheral blood of diabetics associated with age (r = 0.31, P = 0.044), high-sensitive C-reactive protein [hs-CRP] (r = 0.40, P = 0.001), smoking (r = 0.38, P = 0.001), body mass index [BMI] (r = 0.34, P = 0.001), LDL cholesterol (r = 0.28, P = 0.001), glycated hemoglobin [HbA1c] (r = -0.28, P = 0.001), number of CV risk factors (r = 0.26, P = 0.001). In univariate logistic regression analysis we found that level of GDF-15 ≥ 618 pg/mL, hs-CRP ≥7.12 mg/L, HbA1c ≥6.4%, fasting glucose ≥6.7 mmol/L, and BMI ≥27.3 kg/m2 predicted deficiency of both angiopoetic phenotypes of EPCs. In multivariate logistic regression model GDF-15 ≥618 pg/mL demonstrated the best odds ratio values for declining of EPCs in diabetics in comparison with other predictors including BMI, HbA1c and hs-CRP. Conclusion: GDF-15 was remarkably evaluated in type 2 DM population to healthy volunteers, and it was an independent factor that contributes to mobilization and probably proliferation of endothelial precursors with high angiopoetic activity.

Decreased Serum Growth Differentiation Factor 15 Levels After Lifestyle Intervention in Patients With Newly Diagnosed Type 2 Diabetes Mellitus

2020 ◽  
Author(s):  
Xingxing He ◽  
Jiaorong Su ◽  
Xiaojing Ma ◽  
Jingyi Lu ◽  
Yufei Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lifestyle Intervention ◽  
Enzyme Linked Immunosorbent Assay ◽  
Oral Glucose ◽  
Model Assessment ◽  
Newly Diagnosed ◽  
Serum Samples ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

Abstract Background: Recent studies noted that circulating growth differentiation factor 15 (GDF15) were closely related to metabolic states. The study aimed to explore the changes of GDF15 levels and their influencing factors after 4 weeks of lifestyle intervention (LI) or LI combined with breakfast meal replacement (LI+MR) in newly diagnosed type 2 diabetes patients. Methods: A total of 84 patients with available serum samples at both baseline and Week 4 were enrolled in this biomarker substudy. All subjects underwent a 2-hour 75g oral glucose tolerance test at baseline and Week 4. Serum GDF15 levels were determined by a sandwich enzyme-linked immunosorbent assay. Results: After 4-weeks of LI, GDF15 levels overall significantly decreased compared with baseline (P<0.05). ∆GDF15 levels were significantly and negatively associated with baseline GDF15 levels (r=–0.450, P<0.001). The optimal cut-off point of baseline GDF15 levels for predicting a GDF15 decrease after 4-weeks of LI was 904.57 pg/ml, with an area under curve of 0.699. Based on the cut-off point of 900 pg/ml, patients with baseline GDF15 ≥900 pg/ml had significantly decreased GDF15 levels after LI, while those <900 pg/ml had no significant changes. Regression models showed that baseline GDF15 level was an independent positive factor for the improvement of fasting plasma glucose and homeostasis model assessment for insulin resistance only in patients with baseline GDF15 levels ≥900 pg/ml. Conclusions: LI led to significantly decreased GDF15 levels among patients with newly diagnosed type 2 diabetes and its effect was more significant among patients with baseline GDF15 levels ≥900 pg/ml.Trial registration: ClinicalTrials.gov, NCT02248714. Registered 25 September 2014 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02248714?term=NCT02248714&draw=2&rank=1

scholarly journals Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia

2016 ◽  
Vol 40 (1) ◽  
pp. 70 ◽  
Author(s):  
Ji Min Kim ◽  
Min Kyung Back ◽  
Hyon-Seung Yi ◽  
Kyong Hye Joung ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes

Diabetes Care ◽  
2012 ◽  
Vol 35 (11) ◽  
pp. 2340-2346 ◽  
Author(s):  
M. E. Hellemons ◽  
M. Mazagova ◽  
R. T. Gansevoort ◽  
R. H. Henning ◽  
D. de Zeeuw ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor
Sign in / Sign up

Export Citation Format

Share Document