Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Nicotina , Cese del Hábito de Fumar , Dispositivos para Dejar de Fumar Tabaco , Tabaquismo , Humanos , Nicotina/administración & dosificación , Nicotina/efectos adversos , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco/efectos adversos , Tabaquismo/etiología , Tabaquismo/terapia , Estados Unidos , AdolescenteRESUMEN
Peritubular capillary (PTC) rarefaction is commonly detected in chronic kidney disease (CKD) such as hypertensive nephrosclerosis and diabetic nephropathy. Moreover, PTC rarefaction prominently correlates with impaired kidney function and predicts the future development of end-stage renal disease in patients with CKD. However, it is still underappreciated that PTC rarefaction is a pivotal regulator of CKD progression, primarily because the molecular mechanisms of PTC rarefaction have not been well-elucidated. In addition to the established mechanisms (reduced proangiogenic factors and increased anti-angiogenic factors), recent studies discovered significant contribution of the following elements to PTC loss: (1) prompt susceptibility of PTC to injury, (2) impaired proliferation of PTC, (3) apoptosis/senescence of PTC, and (4) pericyte detachment from PTC. Mainly based on the recent and novel findings in basic research and clinical study, this review describes the roles of the above-mentioned elements in PTC loss and focuses on the major factors regulating PTC angiogenesis, the assessment of PTC rarefaction and its surrogate markers, and an overview of the possible therapeutic agents to mitigate PTC rarefaction during CKD progression. PTC rarefaction is not only a prominent histological characteristic of CKD but also a central driving force of CKD progression.
Asunto(s)
Capilares/patología , Fallo Renal Crónico/etiología , Túbulos Renales/irrigación sanguínea , Insuficiencia Renal Crónica/patología , Animales , Apoptosis/fisiología , Capilares/fisiología , Recuento de Células , Senescencia Celular/fisiología , Progresión de la Enfermedad , Células Endoteliales/patología , Humanos , Fallo Renal Crónico/patología , Túbulos Renales/patología , Neovascularización Fisiológica/fisiología , Pericitos/patología , Pericitos/fisiología , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
Peritubular capillary (PTC) rarefaction along with tissue fibrosis is a hallmark of chronic kidney disease (CKD). However, molecular mechanisms of PTC loss have been poorly understood. Previous studies have demonstrated that functional loss of endothelial sirtuin 1 (SIRT1) impairs angiogenesis during development and tissue damage. Here, we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling, which leads to PTC rarefaction and fibrosis following kidney injury. In mice lacking functional SIRT1 in the endothelium (Sirt1 mutant), kidney injury enhanced apoptosis and senescence of PTC endothelial cells with impaired endothelial proliferation and expanded myofibroblast population and collagen deposition. Compared to wild-type kidneys, Sirt1 mutant kidneys up-regulated expression of Delta-like 4 (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target genes), and Notch intracellular domain-1 (NICD1, active form of Notch1) in microvascular endothelial cells (MVECs) post-injury. Sirt1 mutant primary kidney MVECs reduced motility and vascular assembly and enhanced senescence compared to wild-type kidney MVECs. This difference in the phenotype was negated with Notch inhibition. Concurrent stimulation of DLL4 and transforming growth factor (TGF)-ß1 increased trans-differentiation of primary kidney pericytes into myofibroblast more than TGF-ß1 treatment alone. Collectively, these results indicate that endothelial SIRT1 counteracts PTC rarefaction by repression of Notch1 signaling and antagonizes fibrosis via suppression of endothelial DLL4 expression.
Asunto(s)
Capilares/patología , Células Endoteliales/metabolismo , Riñón/lesiones , Riñón/patología , Receptores Notch/metabolismo , Sirtuina 1/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas de Unión al Calcio , Células Endoteliales/patología , Fibrosis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Miofibroblastos/metabolismo , Miofibroblastos/patología , Neovascularización Fisiológica , Pericitos/metabolismo , Pericitos/patología , Transducción de Señal , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
Fibrosis of vital organs is a major public health problem with limited therapeutic options. Mesenchymal cells including microvascular mural cells (pericytes) are major progenitors of scar-forming myofibroblasts in kidney and other organs. Here we show pericytes in healthy kidneys have active WNT/ß-catenin signaling responses that are markedly up-regulated following kidney injury. Dickkopf-related protein 1 (DKK-1), a ligand for the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP-5 and LRP-6) and an inhibitor of WNT/ß-catenin signaling, effectively inhibits pericyte activation, detachment, and transition to myofibroblasts in vivo in response to kidney injury, resulting in attenuated fibrogenesis, capillary rarefaction, and inflammation. DKK-1 blocks activation and proliferation of established myofibroblasts in vitro and blocks pericyte proliferation to PDGF, pericyte migration, gene activation, and cytoskeletal reorganization to TGF-ß or connective tissue growth factor. These effects are largely independent of inhibition of downstream ß-catenin signaling. DKK-1 acts predominantly by inhibiting PDGF-, TGF-ß-, and connective tissue growth factor-activated MAPK and JNK signaling cascades, acting via LRP-6 with associated WNT ligand. Biochemically, LRP-6 interacts closely with PDGF receptor ß and TGF-ß receptor 1 at the cell membrane, suggesting that it may have roles in pathways other than WNT/ß-catenin. In summary, DKK-1 blocks many of the changes in pericytes required for myofibroblast transition and attenuates established myofibroblast proliferation/activation by mechanisms dependent on LRP-6 and WNT ligands but not the downstream ß-catenin pathway.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Pericitos/metabolismo , Pericitos/patología , Animales , Becaplermina , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento del Tejido Conjuntivo/farmacología , Fibrosis , Puntos de Control de la Fase G1 del Ciclo Celular , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pericitos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-sis/farmacología , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacología , Vía de Señalización Wnt/genética , beta Catenina/metabolismoRESUMEN
Chronic kidney disease (CKD) has reached worldwide epidemic proportions and desperately needs new therapies. Peritubular capillary (PTC) rarefaction, together with interstitial fibrosis and tubular atrophy, is one of the major hallmarks of CKD and predicts renal outcome in patients with CKD. PTC endothelial cells (ECs) undergo apoptosis during CKD, leading to capillary loss, tissue hypoxia, and oxidative stress. Although the mechanisms of PTC rarefaction are not well understood, the process of PTC rarefaction depends on multiple events that occur during CKD. These events, which lead to an antiangiogenic environment, include deprivation of EC survival factors, increased production of vascular growth inhibitors, malfunction of ECs, dysfunction of endothelial progenitor cells, and loss of EC integrity via pericyte detachment from the vasculature. In this review, we focus on major factors regulating angiogenesis and EC survival and describe the roles of these factors in PTC rarefaction during CKD and possible therapeutic applications.
Asunto(s)
Capilares/patología , Células Endoteliales/patología , Túbulos Renales/irrigación sanguínea , Insuficiencia Renal Crónica/patología , Proteínas Angiogénicas/metabolismo , Animales , Apoptosis , Capilares/metabolismo , Capilares/fisiopatología , Hipoxia de la Célula , Supervivencia Celular , Progresión de la Enfermedad , Células Endoteliales/metabolismo , Humanos , Neovascularización Fisiológica , Estrés Oxidativo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/terapia , Transducción de SeñalRESUMEN
Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in three-dimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidney microvascular endothelial cells migrated and proliferated less than wild-type microvascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.
Asunto(s)
Lesión Renal Aguda/patología , Capilares/patología , Efrina-B2/metabolismo , Riñón/irrigación sanguínea , Riñón/patología , Receptor EphB4/metabolismo , Lesión Renal Aguda/metabolismo , Animales , Capilares/metabolismo , Células Cultivadas , Fibrosis , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Transducción de SeñalRESUMEN
A 90-year-old man on maintenance hemodialysis was admitted due to severe symptomatic anemia. Biopsies under esophagogastroduodenoscopy demonstrated that the cause of anemia was intermittent blood oozing from multiple gastric hyperplastic polyps. Even after successful eradication of Helicobacter pylori, he showed hypergastrinemia (480 pg/mL) owing to esomeprazole (proton-pump inhibitor) therapy for the past 4.5 years to treat reflux esophagitis. Seven months after we switched esomeprazole to famotidine (H2-receptor antagonist), those gastric polyps and anemia were remarkably ameliorated with lowered gastrin levels. This case indicates that long-term use of a proton-pump inhibitor triggers chronic hypergastrinemia, leading to gastric hyperplastic polyps and subsequent severe anemia.
Asunto(s)
Anemia , Inhibidores de la Bomba de Protones , Masculino , Humanos , Anciano de 80 o más Años , Inhibidores de la Bomba de Protones/efectos adversos , Esomeprazol/efectos adversos , Anemia/inducido químicamente , Biopsia , Hiperplasia/inducido químicamente , Diálisis Renal/efectos adversosRESUMEN
Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this "Hypothesis and Theory" article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.
RESUMEN
Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-ß1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN.
Asunto(s)
Crioglobulinemia/inmunología , Glomerulonefritis Membranoproliferativa/inmunología , Riñón/inmunología , Macrófagos/inmunología , Actinas/metabolismo , Animales , Antígeno CD11b/genética , Colágeno Tipo IV/metabolismo , Crioglobulinemia/complicaciones , Crioglobulinemia/genética , Crioglobulinemia/metabolismo , Crioglobulinemia/patología , Citocinas/genética , Citocinas/metabolismo , Citoprotección , Toxina Diftérica/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Glomerulonefritis Membranoproliferativa/genética , Glomerulonefritis Membranoproliferativa/metabolismo , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/prevención & control , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/inmunología , Hígado/patología , Pulmón/inmunología , Pulmón/patología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas , Proteinuria/inmunología , Proteinuria/prevención & control , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
1. Kidney pericytes were recently identified as collagen Iα1-producing cells in healthy kidney, but the developmental, physiological and pathological roles of kidney pericytes remain poorly understood. Pericytes are stromal-derived cells that envelop and have intimate connections with adjacent capillary endothelial cells (EC). Recent studies in the eye and brain have revealed that pericytes are crucial for angiogenesis, vascular stability and vessel integrity. 2. In response to kidney injury, pericytes promptly migrate away from the capillary wall into the interstitial space. Here, pericytes are activated and differentiate into scar-forming myofibroblasts. In the absence of pericytes, peritubular capillaries are destabilized, leading to vascular regression. Consequently, capillary loss and fibrosis following kidney injury are intimately linked and hinge centrally around pericyte detachment from EC. 3. Kinetic mathematical modelling has demonstrated that pericytes are the major source of myofibroblasts in the fibrotic kidney. Comprehensive genetic fate mapping studies of nephron epithelia or kidney stroma has demonstrated that epithelial cells do not migrate outside of the epithelial compartment to become myofibroblasts; rather, interstitial pericytes are progenitors of scar-forming myofibroblasts. Bidirectional signalling between pericytes and EC is necessary for pericyte detachment from peritubular capillaries. 4. In the present review, we summarize the pathologically vital roles of kidney pericytes in fibrosis, including our new findings. The study of kidney pericytes and endothelial-pericyte cross-talk will identify novel therapeutic targets for currently incurable chronic kidney diseases.
Asunto(s)
Enfermedades Renales/patología , Riñón/patología , Pericitos/patología , Animales , Fibrosis , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Pericitos/metabolismoRESUMEN
BACKGROUND: Expressed in embryonic development, matrix metalloprotein-9 (MMP-9) is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM). While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1) and the down stream signaling. RESULTS: In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK) and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in part, by boost JNK activation in a way to cooperate the cytokine signaling. CONCLUSION: We identified a novel mechanism for MMP-9 expression in response to injury signals, which is mediated by PAK1 activation and stabilization leading JNK activation.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Metaloproteinasa 9 de la Matriz/biosíntesis , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Quinasas p21 Activadas/metabolismo , Western Blotting , Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Humanos , Queratinocitos/metabolismo , Fosforilación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cicatrización de Heridas/fisiologíaAsunto(s)
Volumen Espiratorio Forzado/efectos de los fármacos , Linfangioleiomiomatosis/tratamiento farmacológico , Sirolimus/farmacología , Humanos , Linfangioleiomiomatosis/fisiopatología , Pacientes Desistentes del Tratamiento , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
We isolated adherent fibroblastic cells after collagenase and dispase treatment of human dental pulp. When human dental pulp cells (hDPCs) were cultured in the presence of basic fibroblast growth factor (bFGF), the ratio of hDPCs in the S-phase was significantly higher in comparison with incubation without bFGF. The ratio of hDPCs expressing STRO-1 as a marker of stem cell populations increased approximately eightfold in the presence of bFGF as opposed to that in the absence of bFGF. We demonstrated the characterization and distinctiveness of the hDPCs and showed that, when cultured with the medium containing serum and bFGF, they were highly proliferative and capable of differentiating in vitro into osteoblasts, chondrocytes, and adipocytes. Furthermore, the in vitro differentiation was confirmed at both the protein and gene expression levels. Transplantation of hDPCs -- expanded ex vivo in the presence of bFGF into immunocompromised mice -- revealed the formation of bone, cartilage, and adipose tissue. The donor hDPC-derived cells were labeled in the bone tissues located near the PLGA in the subcutaneous tissues of recipient mice using a human-specific Alu probe. When cultured with a serum-free medium containing bFGF, the hDPCs strongly expressed STRO-1 immunoreactive products and sustained self-renewal, and thus were almost identical in differentiation potential and proliferation activity to hDPCs cultured with the medium containing serum and bFGF. The present results suggest that the hDPCs cultured in the presence of bFGF irrespective of the presence or absence of the bovine serum are rich in mesenchymal stem cells or progenitor cells and useful for cell-based therapies to treat dental diseases.
Asunto(s)
Pulpa Dental/citología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Células Madre/citología , Células Madre/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Adolescente , Adulto , Agrecanos/genética , Agrecanos/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Antígenos de Superficie/metabolismo , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Condrogénesis/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Medios de Cultivo Condicionados/farmacología , Medio de Cultivo Libre de Suero/farmacología , Pulpa Dental/enzimología , Pulpa Dental/trasplante , Pulpa Dental/ultraestructura , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Humanos , Hibridación in Situ , Citometría de Barrido por Láser , Ratones , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogénesis/efectos de los fármacos , Adulto JovenRESUMEN
Epithelial-mesenchymal transition (EMT) is a critical step in renal fibrosis. It has been recently reported that a transcription factor, Twist, plays a pivotal role in metastasis of breast tumors by inducing EMT. In this study, we examined whether Twist relates to renal fibrogenesis including EMT of tubular epithelia, evaluating Twist expression level in the unilateral ureteral obstruction (UUO) model. Kidneys of mice subjected to UUO were harvested 1, 3, 7, and 10 days after obstruction. Compared with control kidneys, Twist mRNA-level significantly increased 3 days after UUO (UUO day 3 kidney) and further augmented until 10 days after UUO. Twist expression increased in tubular epithelia of the dilated tubules and the expanded interstitial areas of UUO kidneys, where cell-proliferating appearances were frequently found in a time-dependent manner. Although a part of tubular cells in whole nephron segment were immunopositive for Twist in UUO day 7 kidneys, tubular epithelia downstream of nephron more frequently expressed Twist than upstream of nephron. In UUO day 7 kidneys, some tubular epithelia were confirmed to coexpress Twist and fibroblast-specific protein-1, a marker for EMT, indicating that Twist is involved in tubular EMT under pathological state. Twist was expressed also in a number of alpha-smooth muscle actin-positive myofibroblasts located in the expanded interstitial area of UUO kidneys. From these findings, the present investigation suggests that Twist is associated with tubular EMT, proliferation of myofibroblasts, and subsequent renal fibrosis in obstructed kidneys.
Asunto(s)
Células Epiteliales/patología , Riñón/patología , Proteína 1 Relacionada con Twist/fisiología , Obstrucción Ureteral/metabolismo , Animales , Biomarcadores/análisis , Proliferación Celular , Fibrosis , Inmunohistoquímica , Riñón/metabolismo , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Mesodermo/patología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/biosíntesis , Factores de Tiempo , Proteína 1 Relacionada con Twist/biosíntesis , Proteína 1 Relacionada con Twist/genética , Proteína wnt2/biosíntesis , Proteína wnt2/genéticaRESUMEN
A 59-year-old-woman received related non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) subsequent to autologous PBSCT in our hospital five years after she was diagnosed as oligo-secretory myeloma. She was admitted to our hospital because of vomiting and grayish diarrhea 4 months after non-myeloablative allogeneic PBSCT (mini-alloPBSCT). Although her initial symptoms improved after admission, she gradually showed thrombocytopenia, anemia, and oliguria during the 2 weeks after admission. Our diagnosis was thrombotic thrombocytopenic purpura (TTP) and acute renal failure (ARF) secondary to mini-alloPBSCT. After cessation of cyclosporine administration, we began to treat her with plasma exchange (PE) and hemodialysis. During the three and a half months after we started PE, the TTP gradually improved. Although PE had been reported to be ineffective for TTP post bone marrow transplantation, we could finally discontinue PE. In contrast, since her anuria continued, she was managed with hemodialysis. One month after PE was started, her activity of von Willebrand factor-cleaving protease was 41% (normal range, >50%) and the ultrasonographic investigation of both kidneys was normal. She could be discharged after four and a half months hospitalization and lived well as an outpatient for a further two months. She died shortly after readmission from multiple organ failure without the relapse of TTP. The patient's clinical course would suggest that TTP post mini-alloPBSCT could be treated with PE in some cases, despite the development of dialysis-requiring severe ARF being a poor prognostic factor.
Asunto(s)
Lesión Renal Aguda/terapia , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/terapia , Diálisis Renal , Lesión Renal Aguda/etiología , Femenino , Humanos , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/etiología , Trasplante HomólogoRESUMEN
Accumulation of myofibroblasts is a hallmark of renal fibrosis. A significant proportion of myofibroblasts has been reported to originate via endothelial-mesenchymal transition. We initially hypothesized that exposing myofibroblasts to the extract of endothelial progenitor cells (EPCs) could reverse this transition. Indeed, in vitro treatment of transforming growth factor-ß1 (TGF-ß1)-activated fibroblasts with EPC extract prevented expression of α-smooth muscle actin (α-SMA); however, it did not enhance expression of endothelial markers. In two distinct models of renal fibrosis-unilateral ureteral obstruction and chronic phase of folic acid-induced nephropathy-subcapsular injection of EPC extract to the kidney prevented and reversed accumulation of α-SMA-positive myofibroblasts and reduced fibrosis. Screening the composition of EPC extract for cytokines revealed that it is enriched in leukemia inhibitory factor (LIF) and vascular endothelial growth factor. Only LIF was capable of reducing fibroblast-to-myofibroblast transition of TGF-ß1-activated fibroblasts. In vivo subcapsular administration of LIF reduced the number of myofibroblasts and improved the density of peritubular capillaries; however, it did not reduce the degree of fibrosis. A receptor-independent ligand for the gp130/STAT3 pathway, hyper-interleukin-6 (hyper-IL-6), not only induced a robust downstream increase in pluripotency factors Nanog and c-Myc but also exhibited a powerful antifibrotic effect. In conclusion, EPC extract prevented and reversed fibroblast-to-myofibroblast transition and renal fibrosis. The component of EPC extract, LIF, was capable of preventing development of the contractile phenotype of activated fibroblasts but did not eliminate TGF-ß1-induced collagen synthesis in cultured fibroblasts and models of renal fibrosis, whereas a receptor-independent gp130/STAT3 agonist, hyper-IL-6, prevented fibrosis. In summary, these studies, through the evolution from EPC extract to LIF and then to hyper-IL-6, demonstrate the instructive role of microenvironmental cues and may provide in the future a facile strategy to prevent and reverse renal fibrosis. Stem Cells Translational Medicine 2017;6:992-1005.
Asunto(s)
Microambiente Celular , Riñón/patología , Células 3T3 , Animales , Microambiente Celular/efectos de los fármacos , Quimiocinas/metabolismo , Receptor gp130 de Citocinas/metabolismo , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibrosis , Interleucina-6/farmacología , Factor Inhibidor de Leucemia/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miofibroblastos/citología , Miofibroblastos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation.