RESUMO
Repeated intravesical injections of autologous platelet-rich plasma (PRP) have been shown to improve symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS); however, there is a paucity of objective evidence of the effectiveness of this therapy. In this study, we investigated the changes in urinary markers after PRP treatment. Forty patients with IC/BPS who were refractory to conventional therapy received four injections of PRP at monthly intervals; 10 mL PRP solution with 2.5 times the peripheral blood platelet concentration was used. Urine levels of thirteen functional proteins, growth factors, and cytokines were assessed at baseline and at the 4th PRP injection. The clinical parameters included visual analog scale (VAS) pain score, daily urinary frequency, nocturia episodes, functional bladder capacity, and global response assessment (GRA). The GRA and symptom score significantly decreased post-treatment. In patients with GRA ≥ 2, the success rates at 1 month and at 3 months after the 4th PRP injection were 70.6% and 76.7%, respectively. The VAS pain score, frequency, and nocturia showed a significant decrease (all p < 0.05). Urinary levels of nerve growth factor, matrix metalloproteinase-13, and vascular endothelial growth factor significantly decreased post-treatment (p = 0.043, p = 0.02, and p = 0.000, respectively); platelet-derived growth factor-AB showed a significant increase (p = 0.004) at the 4th PRP treatment compared with baseline. In this study, repeated intravesical PRP injections provided significant symptom improvement in IC/BPS patients with concomitant changes in the related biomarker levels.Trial registration: ClinicalTrial.gov: NCT03104361; IRB: TCGH 105-48-A.
Assuntos
Biomarcadores/urina , Cistite Intersticial/terapia , Plasma Rico em Plaquetas , Administração Intravesical , Idoso , Cistite Intersticial/urina , Feminino , Humanos , Masculino , Metaloproteinase 13 da Matriz/urina , Pessoa de Meia-Idade , Fator de Crescimento Neural/urina , Fator de Crescimento Derivado de Plaquetas/urina , Estudos Prospectivos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/urina , Escala Visual AnalógicaRESUMO
Persistent high concentration of glucose causes cellular stress and damage in diabetes via derangement of gene expressions. We previously reported high glucose activates hypoxia-inducible factor-1αand downstream gene expression in mesangial cells, leading to an extracellular matrix expansion in the glomeruli. A glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP) is a key mediator for such perturbation of gene regulation. To provide insight into glucose-mediated gene regulation in mesangial cells, we performed chromatin immunoprecipitation followed byDNAmicroarray analysis and identified platelet-derived growth factor-C (PDGF-C) as a novel target gene of ChREBP In streptozotocin-induced diabetic mice, glomerular cells showed a significant increase inPDGF-C expression; the ratio ofPDGF-C-positive cells to the total number glomerular cells demonstrated more than threefold increase when compared with control animals. In cultured human mesangial cells, high glucose enhanced expression ofPDGF-C protein by 1.9-fold. Knock-down of ChREBPabrogated this induction response. UpregulatedPDGF-C contributed to the production of typeIVand typeVIcollagen, possibly via an autocrine mechanism. Interestingly, urinaryPDGF-C levels in diabetic model mice were significantly elevated in a fashion similar to urinary albumin. Taken together, we hypothesize that a high glucose-mediated induction ofPDGF-C via ChREBPin mesangial cells contributes to the development of glomerular mesangial expansion in diabetes, which may provide a platform for novel predictive and therapeutic strategies for diabetic nephropathy.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Linfocinas/metabolismo , Células Mesangiais/metabolismo , Proteínas Nucleares/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Sítios de Ligação , Linhagem Celular , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Diabetes Mellitus Experimental/sangue , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Humanos , Linfocinas/genética , Linfocinas/urina , Masculino , Células Mesangiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/urina , Regiões Promotoras Genéticas , Ligação Proteica , Interferência de RNA , Fatores de Tempo , Fatores de Transcrição/genética , Transfecção , Regulação para CimaRESUMO
STUDY GOAL: The aim of the study was to assess the role of the kidney in systemic elimination of IL-6 and growth factors (PDGF, TGF-ß) by comparison of their concentrations in renal arteries and veins, peripheral veins and urine. MATERIAL AND METHODS: 30 brain-dead kidney donors were included in the study. Samples were obtained during the harvesting procedure. 10 healthy volunteers served as controls. A mathematical model of elimination of investigated proteins from systemic circulation was developed. The elimination ratio (ER) formula indicates the predominance of renal synthesis or degradation and also quantifies the renal uptake (UR) and renal pass (PR) of investigated proteins. Serum levels of investigated proteins were estimated using an immunoenzymatic method (ELISA). RESULTS: Renal IL-6 uptake ratio (UR) amounted to 6.6%, elimination ratio (ER) amounted to 6.4% and pass ratio (PR) amounted to 0.2%. PDGF ratios amounted to 5.1%, 5.0% and 0.1% and TGF-ß ratios amounted to -9%, -9% and 0%, respectively. CONCLUSIONS: The kidney takes part in the elimination of IL-6 and PDGF from systemic circulation. The kidney does not take part in the elimination of TGF-ß.
Assuntos
Interleucina-6/urina , Rim/metabolismo , Fator de Crescimento Derivado de Plaquetas/urina , Fator de Crescimento Transformador beta/urina , Adulto , Creatinina/urina , Feminino , Humanos , Interleucina-6/sangue , Masculino , Doadores de Tecidos , Fator de Crescimento Transformador beta/sangueRESUMO
OBJECTIVE: Acute glycemic variability contributes to diabetic complications potentially through induction of inflammation. Our objective was to determine whether acute hyperglycemia affects urinary secretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes. RESEARCH DESIGN AND METHODS: Blood pressure, renal hemodynamics (inulin and paraaminohippurate clearances), and urine samples were obtained after 6 h of clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l) on two consecutive days in subjects with type 1 diabetes (n = 25). Forty-two urinary cytokines/chemokines were measured using a Luminex platform. RESULTS: Clamped hyperglycemia produced an expected increase in glomerular filtration rate (131 ± 4 to 148 ± 8 ml/min/1.73 m²). Clamped hyperglycemia was associated with significant increases in urinary eotaxin, fibroblast growth factor-2, granulocyte-macrophage colony-stimulating factor, interferon-α 2, interleukin-2 and -12, monocyte chemoattractant protein-3, macrophage-derived chemokine, macrophage inflammatory protein-1α, platelet-derived growth factor, tumor necrosis factor-α, and CD40 ligand (P < 0.05). CONCLUSIONS: Acute hyperglycemia results in increased urinary excretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes, and this may contribute to kidney injury.
Assuntos
Quimiocinas/urina , Citocinas/urina , Diabetes Mellitus Tipo 1/urina , Hiperglicemia/urina , Adolescente , Adulto , Quimiocina CCL7/urina , Feminino , Taxa de Filtração Glomerular , Humanos , Interferon-alfa/urina , Interleucina-2/urina , Masculino , Fator de Crescimento Derivado de Plaquetas/urina , Fator de Necrose Tumoral alfa/urina , Adulto JovemRESUMO
OBJECTIVE: To investigate urinary excretion of platelet-derived growth factor-BB (PDGF-BB) during the different stages of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) as well as its clinical significance. METHODS: Sixty-five cases with T2DM were divided into three groups: normoalbuminuric group [N-UAlb; urine albumin excretion (UAE) <30 mg/24 h, n=25], microalbuminuric group [M-UAlb; UAE 30-300 mg/24 h, n=20], and macroalbuminuric group [L-UAlb; UAE >300 mg/ 24 h, n=20]. The urinary excretion rates of PDGF-BB were determined by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) in all the cases and 27 subjects of control. RESULTS: The excretion rates of PDGF-BB in T2DM groups were markedly higher than that in control (P<0.001). Moreover, the excretion rates of PDGF-BB increased with the increase of UAE and there were significant differences among the three groups (P<0.05) except the groups of M-UAlb and L-UAlb. Urinary PDGF-BB was also positively correlated with UAE, triglyceride (TG), cholesterol (CHO), low-density lipoprotein (LDL) and negatively correlated with creatinine clearance (Ccr), high-density lipoprotein (HDL), while had no significance correlated with glycohemoglobin A1c (HbA1c). CONCLUSION: PDGF-BB might play a very important role in the initiation and progression of DN. Measurements of urine PDGF-BB in T2DM could be used for early diagnosis of diabetic renal dysfunction.
Assuntos
Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/epidemiologia , Fator de Crescimento Derivado de Plaquetas/urina , Adulto , Idoso , Albuminúria/epidemiologia , Análise de Variância , Becaplermina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-sis , Valores de ReferênciaRESUMO
OBJECTIVE: To investigate the clinical implication of platelet-derived growth factor (PDGF)-D and PDGF-beta in IgA nephropathy in childhood. METHODS: Forty-seven children with IgA nephropathy and 26 controls were enrolled for study, and their serum, urine and renal biopsy specimens were examined. The patients were divided into control group [including serum, urine specimens of 13 healthy children and 13 renal biopsy samples of non-IgA nephropathy in children], mild proliferation (MP) group (13 patients), focal proliferation (FP) group (19 patients), and proliferation sclerosis (PS) group (15 patients). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to determine contents of PDGF-D, PDGF-beta and PDGF-B in blood, urine and renal tissues. The levels of 24-hour urinary protein excretion, serum albumin (Alb), serum blood urea nitrogen (BUN) and creatinine (Cr) were also determined. RESULTS: Compared with control group, levels of PDGF-D and PDGF-B were progressively elevated in blood and urine of IgA nephropathy children with increase in severity of glomerular damage (all P<0.01). Serum as well as urinary PDGF-D and PDGF-B levels were positively correlated with 24-hour urinary protein excretion (PDGF-D blood: r=0.546, urine: r=0.760; PDGF-B blood: r=0.634, urine: r=0.577, respectively, P<0.01), while negatively correlated with serum Alb levels in IgA nephropathy patients (PDGF-D blood: r=-0.649, urine: r=-0.528; PDGF-B blood: r=-0.613, urine: r=-0.531, respectively, P<0.01). Contents of PDGF-D and PDGF-beta in renal tissue were much higher than those of control group (P<0.01). Along with the increase in severity of glomerular pathology, their contents increased gradually. PDGF-B was only significantly expressed in renal tissue in FP group and PS group. CONCLUSION: PDGF-D might significantly enhance the development of mesangial proliferation and tubulointerstitial fibrosis. In comparison with PDGF-B, PDGF-D appears to reflect more sensitive to the severity and prognosis of IgA nephropathy.
Assuntos
Glomerulonefrite por IGA/metabolismo , Linfocinas/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Adolescente , Criança , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/urina , Humanos , Rim/metabolismo , Rim/patologia , Linfocinas/sangue , Linfocinas/urina , Masculino , Fator de Crescimento Derivado de Plaquetas/urina , Proteínas Proto-Oncogênicas c-sis/sangue , Proteínas Proto-Oncogênicas c-sis/urinaRESUMO
We studied the urinary excretion of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor-BB (PDGF) and fibronectin (FN) in 104 patients (52 normoalbuminuric, 24 microalbuminuric, and 28 with overt diabetic nephropathy) with insulin-dependent diabetes mellitus (IDDM) of a long duration and in 30 non-diabetic controls. IDDM patients had higher urinary excretion of TGF-beta 1, PDGF and FN compared to controls. Urinary excretion of TGF-beta 1 and PDGF was elevated in all IDDM subgroups, while FN excretion was significantly increased only in patients with macroalbuminuria. Urinary excretion of TGF-beta 1 and FN did not differ between normoalbuminuric IDDM patients with long duration of diabetes, a group at low risk of ever developing diabetic nephropathy, and IDDM patients with incipient or overt diabetic nephropathy. Excretion of PDGF was significantly higher in patients with micro- and macroalbuminuria compared to normoalbuminuric patients, but there was a considerable overlap between the groups. In conclusion, although longitudinal follow-up studies are needed to further clarify the issue, our results in long-standing IDDM do not support a hypothesis of urinary excretion of TGF-beta 1, PDGF or FN to predict development of diabetic nephropathy.
Assuntos
Anticoagulantes/urina , Diabetes Mellitus Tipo 2/urina , Fibronectinas/urina , Fator de Crescimento Derivado de Plaquetas/urina , Fator de Crescimento Transformador beta/urina , Adulto , Albuminúria/urina , Becaplermina , Nefropatias Diabéticas/urina , Feminino , Humanos , Masculino , Proteínas Proto-Oncogênicas c-sis , Proteínas Recombinantes/urinaAssuntos
Expressão Gênica , Rejeição de Enxerto/fisiopatologia , Transplante de Rim/fisiologia , Fator de Crescimento Derivado de Plaquetas/biossíntese , Fator de Crescimento Transformador beta/biossíntese , Doença Crônica , Rejeição de Enxerto/patologia , Rejeição de Enxerto/urina , Humanos , Hibridização In Situ , Transplante de Rim/imunologia , Transplante de Rim/patologia , Fator de Crescimento Derivado de Plaquetas/urina , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Fator de Crescimento Transformador beta/urina , Transplante HomólogoRESUMO
Our enzyme-linked immunosorbent assay (ELISA) for measuring human platelet-derived growth factor (PDGF) detects nanogram quantities (ranging from 0.007 to 16 ng/100 microL) in purified PDGF standards. This assay is sensitive enough for studying plasma and urine. The range in normal volunteers was 0.6 to 2.3 micrograms/L for platelet-poor plasma and 1.4 to 3.3 micrograms/L for urine. We determined PDGF levels in the circulation (outside platelets) in patients with myeloproliferative diseases. Platelet-poor plasma and urine PDGF were significantly elevated in patients with myelofibrosis (6.2 +/- 2.0 micrograms/L for plasma; 7.8 +/- 2.4 micrograms/L for urine) and essential thrombocythemia (5.5 +/- 1.5 micrograms/L for plasma; 11.4 +/- 2.2 micrograms/L for urine), but not in patients with chronic myelogenous leukemia (2.1 +/- 0.4 micrograms/L for plasma; 2.8 +/- 1.2 micrograms/L for urine). Polycythemia vera produced an intermediate pattern: although plasma PDGF was within the normal range (2.1 +/- 0.2 micrograms/L), urine levels were increased (3.7 +/- 0.6 micrograms/L). These results show that PDGF is increased in the circulation in some but not all myeloproliferative diseases, and suggest that this is due to abnormal in vivo release from either megakaryocytes in the bone marrow or circulating platelets.