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1.
Cells ; 12(12)2023 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-37371125

RESUMEN

Cisplatin is one of the most effective chemotherapeutic agents strongly associated with nephrotoxicity. Tubular adult renal progenitor cells (tARPC) can regenerate functional tubules and participate in the repair processes after cisplatin exposition. This study investigated the molecular mechanisms underlying the protective effect of tARPC on renal epithelium during cisplatin nephrotoxicity. By performing a whole-genome transcriptomic analysis, we found that tARPC, in presence of cisplatin, can strongly influence the gene expression of renal proximal tubular cell [RPTEC] by inducing overexpression of CYP1B1, a member of the cytochrome P450 superfamily capable of metabolizing cisplatin and of hypoxia/cancer-related lncRNAs as MIR210HG and LINC00511. Particularly, tARPC exerted renoprotection and regeneration effects via extracellular vesicles (EV) enriched with CYP1B1 and miR-27b-3p, a well-known CYP1B1 regulatory miRNA. The expression of CYP1B1 by tARPC was confirmed by analyzing biopsies of cisplatin-treated renal carcinoma patients that showed the colocalization of CYP1B1 with the tARPC marker CD133. CYP1B1 was also overexpressed in urinary EV purified from oncologic patients that presented nephrotoxicity episodes after cisplatin treatment. Interestingly CYP1B1 expression significantly correlated with creatinine and eGFR levels. Taken together, our results show that tARPC are able to counteract cisplatin-induced nephrotoxicity via CYP1B1 release through EV. These findings provide a promising therapeutic strategy for nephrotoxicity risk assessment that could be related to abundance of renal progenitors.


Asunto(s)
Cisplatino , Riñón , MicroARNs , Células Madre , Adulto , Humanos , Cisplatino/efectos adversos , Cisplatino/metabolismo , Cisplatino/farmacología , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Regulación hacia Abajo/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Células Madre/metabolismo
2.
G Ital Cardiol (Rome) ; 23(10): 793-812, 2022 Oct.
Artículo en Italiano | MEDLINE | ID: mdl-36169130

RESUMEN

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.


Asunto(s)
Cardiología , Enfermedades Cardiovasculares , Nefrología , Insuficiencia Renal Crónica , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/prevención & control , Consenso , Medios de Contraste , Humanos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/prevención & control
3.
G Ital Cardiol (Rome) ; 23(9): 716-727, 2022 Sep.
Artículo en Italiano | MEDLINE | ID: mdl-36039723

RESUMEN

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.


Asunto(s)
Síndrome Cardiorrenal , Cardiología , Enfermedades Cardiovasculares , Nefrología , Insuficiencia Renal Crónica , Síndrome Cardiorrenal/etiología , Síndrome Cardiorrenal/prevención & control , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Consenso , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo
4.
Stem Cells ; 40(10): 963-975, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-35922038

RESUMEN

The long non-coding RNAs (lncRNA) play an important role in several biological processes, including some renal diseases. Nevertheless, little is known about lncRNA that are expressed in the healthy kidneys and involved in renal cell homeostasis and development, and even less is known about lncRNA involved in the maintenance of human adult renal stem/progenitor cells (ARPCs) that have been shown to be very important for renal homeostasis and repair processes. Through a whole-genome transcriptome screening, we found that the HOTAIR lncRNA is highly expressed in renal progenitors and potentially involved in cell cycle and senescence biological processes. By CRISPR/Cas9 genome editing, we generated HOTAIR knockout ARPC lines and established a key role of this lncRNA in ARPC self-renewal properties by sustaining their proliferative capacity and limiting the apoptotic process. Intriguingly, the HOTAIR knockout led to the ARPC senescence and to a significant decrease in the CD133 stem cell marker expression which is an inverse marker of ARPC senescence and can regulate renal tubular repair after the damage. Furthermore, we found that ARPCs expressed high levels of the α-Klotho anti-aging protein and especially 2.6-fold higher levels compared to that secreted by renal proximal tubular cells (RPTECs). Finally, we showed that HOTAIR exerts its function through the epigenetic silencing of the cell cycle inhibitor p15 inducing the trimethylation of the histone H3K27. Altogether, these results shed new light on the mechanisms of regulation of these important renal cells and may support the future development of precision therapies for kidney diseases.


Asunto(s)
ARN Largo no Codificante , Adulto , Humanos , Senescencia Celular/genética , Histonas/metabolismo , Riñón/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Células Madre/metabolismo , Proteínas Klotho
5.
Front Immunol ; 13: 840146, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35355984

RESUMEN

Our immune system actively fights bacteria and viruses, and it must strike a delicate balance between over- and under-reaction, just like Daedalus and Icarus in Greek mythology, who could not escape their imprisonment by flying too high or too low. Both human amniotic epithelial and mesenchymal stromal cells and the conditioned medium generated from their culture exert multiple immunosuppressive activities. They have strong immunomodulatory properties that are influenced by the types and intensity of inflammatory stimuli present in the microenvironment. Notably, very recently, the immunomodulatory activity of human adult renal stem/progenitor cells (ARPCs) has been discovered. ARPCs cause a decrease in Tregs and CD3+ CD4- CD8- (DN) T cells in the early stages of inflammation, encouraging inflammation, and an increase in the late stages of inflammation, favoring inflammation quenching. If the inflammatory trigger continues, however, ARPCs cause a further increase in DN T cells to avoid the development of a harmful inflammatory state. As in the flight of Daedalus and Icarus, who could not fly too high or too low to not destroy their wings by the heat of the sun or the humidity of the sea, in response to an inflammatory environment, stem cells seem to behave by paying attention to regulating T cells in the balance between immune tolerance and autoimmunity. Recognizing the existence of both suppressive and stimulatory properties, and the mechanisms that underpin the duality of immune reaction, will aid in the development of active immunotherapeutic approaches that manipulate the immune system to achieve therapeutic benefit.


Asunto(s)
Células Madre Mesenquimatosas , Adulto , Animales , Humanos , Inmunomodulación , Inflamación , Células Madre , Linfocitos T
6.
Front Immunol ; 12: 605212, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33868226

RESUMEN

Sepsis-induced acute kidney injury (AKI) is a frequent complication in critically ill patients, refractory to conventional treatments. Aberrant activation of innate immune system may affect organ damage with poor prognosis for septic patients. Here, we investigated the efficacy of polymethyl methacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune activation in a swine model of LPS-induced AKI. After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic Complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by Real-time PCR. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative Complement pathways were found in endotoxemic animals. PMMA-CVVH treatment significantly reduced tissue and systemic Complement activation limiting renal damage and fibrosis. By microarray analysis, we identified 711 and 913 differentially expressed genes with a fold change >2 and a false discovery rate <0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process. Our data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in LPS-induced AKI.


Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Activación de Complemento/efectos de los fármacos , Hemofiltración , Lipopolisacáridos/efectos adversos , Polimetil Metacrilato/administración & dosificación , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/mortalidad , Animales , Biomarcadores , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Expresión Génica , Hemofiltración/efectos adversos , Hemofiltración/métodos , Humanos , Inmunohistoquímica , Mediadores de Inflamación , Pruebas de Función Renal , Diálisis Renal , Sepsis/complicaciones , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Porcinos , Resultado del Tratamiento
7.
J Nephrol ; 34(6): 1989-1997, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33761122

RESUMEN

BACKGROUND: Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. METHODS: The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). RESULTS: Eight hundred and forty-seven genes were differentially expressed in patients treated with  on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial Growth Factor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis  were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. CONCLUSIONS: Our data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.


Asunto(s)
Aterosclerosis , Hemodiafiltración , Aterosclerosis/diagnóstico , Aterosclerosis/genética , Estudios Transversales , Humanos , Leucocitos Mononucleares , Diálisis Renal , Factor C de Crecimiento Endotelial Vascular
8.
Int J Mol Sci ; 22(1)2020 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-33383950

RESUMEN

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.


Asunto(s)
Células Madre Adultas/metabolismo , Riñón/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Biomarcadores , Proliferación Celular , Quimiocinas/metabolismo , Humanos , Inmunomodulación , Inmunofenotipificación , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Receptor Toll-Like 2/metabolismo
9.
Hypertension ; 75(1): 71-78, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31760884

RESUMEN

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.


Asunto(s)
Presión Sanguínea/genética , Hipertensión/etiología , Adolescente , Alelos , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hipertensión/genética , Masculino , Polimorfismo de Nucleótido Simple
10.
FASEB J ; 33(10): 10753-10766, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31268775

RESUMEN

Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (ECs) acquired a fibroblast-like phenotype and contributed to myofibroblast generation through the endothelial-to-mesenchymal transition (EndMT) process. Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI but little is known about their effects on ECs. Following LPS exposure, ECs proliferated, decreased EC markers CD31 and vascular endothelial cadherin, and up-regulated myofibroblast markers, collagen I, and vimentin. The coculture with ARPCs normalized the EC proliferation rate and abrogated the LPS-induced EndMT. The gene expression analysis showed that most of the genes modulated in LPS-stimulated ARPCs belong to cell activation and defense response pathways. We showed that the ARPC-specific antifibrotic effect is exerted by the secretion of CXCL6, SAA4, and BPIFA2 produced after the anaphylatoxin stimulation. Next, we investigated the molecular signaling that underlies the ARPC protective mechanism and found that renal progenitors diverge from differentiated tubular cells and ECs in myeloid differentiation primary response 88-independent pathway activation. Finally, in a swine model of LPS-induced AKI, we observed that activated ARPCs secreted CXCL6, SAA4, and BPIFA2 as a defense response. These data open new perspectives on the treatment of both sepsis- and endotoxemia-induced AKI, suggesting an underestimated role of ARPCs in preventing endothelial dysfunction and novel strategies to protect the endothelial compartment and promote kidney repair.-Sallustio, F., Stasi, A., Curci, C., Divella, C., Picerno, A., Franzin, R., De Palma, G., Rutigliano, M., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Pertosa, G. B., Castellano, G., Gallone, A., Gesualdo, L. Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides.


Asunto(s)
Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Células Madre Adultas/patología , Quimiocina CXCL6/metabolismo , Células Endoteliales/patología , Proteínas y Péptidos Salivales/metabolismo , Proteína Amiloide A Sérica/metabolismo , Lesión Renal Aguda/genética , Células Madre Adultas/efectos de los fármacos , Células Madre Adultas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Lipopolisacáridos/toxicidad , Factor 88 de Diferenciación Mieloide/metabolismo , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Regeneración/fisiología , Transducción de Señal/efectos de los fármacos , Sus scrofa
11.
Int J Mol Sci ; 20(15)2019 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-31357597

RESUMEN

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRß expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-ß, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRß and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-ß signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-ß and underwent PMT also upon TGF-ß receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.


Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Proteínas de Fase Aguda/metabolismo , Proteínas Portadoras/metabolismo , Transdiferenciación Celular , Glicoproteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Pericitos/metabolismo , Receptor Toll-Like 4/metabolismo , Lesión Renal Aguda/patología , Animales , Biopsia , Transdiferenciación Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Endotoxinas/efectos adversos , Fibrosis , Inmunohistoquímica , Modelos Biológicos , Miofibroblastos/citología , Porcinos
12.
Nephrol Dial Transplant ; 33(1): 65-75, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28992140

RESUMEN

Background: Inflammation and immune system alterations contribute to bone damage in many pathologies by inducing the differentiation of osteoclasts (OCs), the bone resorbing cells. This link is largely unexplored in chronic kidney disease (CKD) and haemodialysis (HD) patients, in which reduced renal function is accompanied by an increased inflammatory state and skeletal abnormality. Methods: We used ex vivo culture experiments to investigate the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) of CKD and HD patients, focusing on immune cell subsets and inflammatory cytokines such as LIGHT and receptor activator of nuclear factor κB ligand (RANKL). Results: We observed spontaneous osteoclastogenesis with a significant increase in OC formation and bone resorbing activity in late-stage CKD and HD patients when compared with early-stage CKD patients and healthy donors, likely due to an increased expression of RANKL and LIGHT (homologous to Lymphotoxins exhibiting Inducible expression and competing with herpes simplex virus Glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes) in PBMCs. Specific inhibition of these cytokines in PBMCs isolated from CKD stages 3b-5 and HD patients induced the reduction of OC formation in vitro. The phenotypic characterization of peripheral blood cells revealed a significant increase of OC precursors (CD14+CD11b+CD51/61+) and CD14+CD16+ monocytes in advanced CKD and HD patients compared with the control group. Conclusions: Our results suggest that circulating inflammatory monocytes from advanced CKD or HD patients trans differentiate into OCs in vitro and play a relevant role in mineral bone disorders and that LIGHT and RANKL represent new potential therapeutic targets in these settings.


Asunto(s)
Resorción Ósea/etiología , Diferenciación Celular/inmunología , Inflamación/complicaciones , Leucocitos Mononucleares/patología , Osteoclastos/patología , Insuficiencia Renal Crónica/etiología , Resorción Ósea/patología , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Inflamación/fisiopatología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Osteoclastos/inmunología , Ligando RANK/metabolismo , Insuficiencia Renal Crónica/patología
13.
Nephrol Dial Transplant ; 32(1): 24-31, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27387474

RESUMEN

Sepsis remains a serious cause of morbidity and mortality in critically ill patients, with limited therapeutic options available. Of the several disorders connected with sepsis, acute kidney injury (AKI) is one of the major complications. The pathophysiology of sepsis-induced AKI is characterized by severe inflammation in renal parenchyma with endothelial dysfunction, intra-glomerular thrombosis and tubular injury. Endothelial dysfunction is regulated by several mechanisms implicated in cellular de-differentiation, such as endothelial-to-mesenchymal transition (EndMT). Gram-negative bacteria and their cell wall component lipopolysaccharides (LPSs) are frequently involved in the pathogenesis of AKI. The host recognition of LPS requires a specific receptor, which belongs to the Toll-like receptor (TLR) family of proteins, called TLR4, and two carrier proteins, namely the LPS-binding protein (LBP) and cluster of differentiation 14 (CD14). In particular, LBP is released as a consequence of Gram-negative infection and maximizes the activation of TLR4 signalling. Recent findings regarding the emerging role of LBP in mediating sepsis-induced AKI, and the possible beneficial effects resulting from the removal of this endogenous adaptor protein, will be discussed in this review.


Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Proteínas de Fase Aguda/metabolismo , Proteínas Portadoras/metabolismo , Lipopolisacáridos/efectos adversos , Glicoproteínas de Membrana/metabolismo , Sepsis/complicaciones , Lesión Renal Aguda/patología , Animales , Humanos , Transducción de Señal
14.
J Cardiovasc Med (Hagerstown) ; 18(5): 359-365, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-26657082

RESUMEN

AIMS: Acute kidney injury (AKI) is a common complication following cardiac surgery. Cardiopulmonary bypass elicits coagulation and inflammation activation and oxidative stress, all involved in AKI but never simultaneously assessed. We aimed to evaluate relations between oxidative stress, inflammatory and coagulation systems activation and postoperative renal function in patients with normal preoperative renal function. METHODS: Forty-one high-risk patients (EuroSCORE >6 and preoperative haemoglobin <12 g/dl in women and <13 g/dl in men) were prospectively enrolled. Prothrombin fragment 1.2 (coagulation marker), interleukin-6 and interleukin-10 (pro/anti-inflammatory markers) and 8-oxo-2'-deoxyguanosine (oxidative stress marker) were evaluated until postoperative day 5. RESULTS: Patients were divided into two groups according to estimated glomerular filtration rate reduction observed postoperatively (reduction <25% in 26 patients: NO-AKI group; reduction >25% in 15 patients: AKI group). No differences were found for inflammatory markers. Oxidative stress slightly increased in the AKI group. Twenty-four hours after the operation prothrombin fragment 1.2 levels were significantly higher in the AKI group (506.6 ±â€Š548 vs. 999 ±â€Š704.1 pmol/l; P = 0.018), and they were independently associated with estimated glomerular filtration rate reduction, with an area under the receiving operating characteristic of 0.744. CONCLUSION: Thrombin generation is higher in patients with renal function worsening, and it is an independent risk factor for AKI in patients with anaemia, possibly leading to microcirculation impairment and tubular cells damage.


Asunto(s)
Lesión Renal Aguda/etiología , Coagulación Sanguínea , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Mediadores de Inflamación/sangre , Inflamación/etiología , Riñón/fisiopatología , Lesión Renal Aguda/sangre , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/fisiopatología , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/complicaciones , Área Bajo la Curva , Biomarcadores/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Masculino , Estrés Oxidativo , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Estudios Prospectivos , Protrombina , Curva ROC , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
15.
Nephrol Dial Transplant ; 32(9): 1540-1549, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-27915246

RESUMEN

BACKGROUND: The aim of this study was to investigate neutrophil activation and its role in long pentraxin-3 (PTX3) release and oxidative stress generation during haemodialysis (HD) and to correlate neutrophil PTX3 and oxidant expression with endothelial dysfunction. METHODS: Forty-seven uraemic patients on stable HD, 12 healthy subjects and 15 patients with congestive heart failure (New York Heart Association classes III and IV) were enrolled. Neutrophil PTX3 protein expression was evaluated by confocal microscopy. l -selectin expression, intracellular PTX3 localization and reactive oxygen species (ROS) generation in human neutrophils were measured by flow cytometry. NADPH-dependent superoxide generation was investigated by chemiluminescence. PTX3 plasma concentrations were measured by ELISA. Endothelial dysfunction was studied by flow-mediated dilation (FMD). RESULTS: The low baseline levels of FMD significantly improved after HD, but worsened by 24 h. A significant up-regulation of PTX3 protein expression, localized within secondary granules, was detected in neutrophils isolated at 30 and 240 min of HD, along with an increase in l -selectin expression. The up-regulation in intracellular PTX3 in neutrophils was associated with a significant increase in PTX3 plasma concentrations at 240 min. HD increased ROS production and NADPH oxidase activity in neutrophils. In a univariate analysis, pre-treatment with FMD was inversely correlated with PTX3 expression and ROS generation in neutrophils. In a multivariate analysis, both circulating pre-HD PTX3 and intracellular ROS generation by neutrophils were independent predictors of abnormal FMD. CONCLUSIONS: Neutrophil overexpression of PTX3 is associated with ROS overproduction and endothelial dysfunction and may represent an emerging marker of vascular damage progression in HD patients.


Asunto(s)
Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Endotelio Vascular/patología , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Diálisis Renal , Componente Amiloide P Sérico/metabolismo , Enfermedades Vasculares/patología , Endotelio Vascular/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Activación Neutrófila , Estrés Oxidativo , Regulación hacia Arriba , Enfermedades Vasculares/sangre
16.
G Ital Nefrol ; 32(2)2015.
Artículo en Italiano | MEDLINE | ID: mdl-26219120
17.
Medicine (Baltimore) ; 93(27): e183, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25501064

RESUMEN

Malignancies are one of the main causes of mortality in diabetic patients; however, to date, very limited data have been reported on the specific influence of type 2 diabetes mellitus (T2DM) on the survival of patients with renal cell carcinoma (RCC). In the present long-term retrospective study, we investigated whether T2DM may influence the overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in patients with surgically treated RCC. Medical records of 924 patients treated by radical or partial nephrectomy for sporadic, unilateral RCC were reviewed. Patients with type-1 DM and with T2 DM receiving insulin treatment were excluded. Survival estimates were calculated according to the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox regression model.Of the 924 RCC patients, 152 (16.5%) had T2DM. Mean follow-up was 68.5 months. Mean OS was 41.3 and 96.3 months in T2DM and non-T2DM patients, respectively (P < 0.0001).The estimated CSS rates at 1, 3, and 5 years in T2DM versus non-T2DM patients were 63.4% versus 76.7%, 30.4% versus 56.6%, and 16.3% versus 48.6%, respectively (P = 0.001). Mean PFS was significantly lower (31.5 vs 96.3 months; P < 0.0001) in the T2DM group. At multivariate analysis, T2DM was an independent adverse prognostic factor for OS (hazard ratio [HR]  = 3.44; 95% confidence interval [CI]:2.40-4.92), CSS (HR = 6.39; 95% CI: 3.78-10.79), and PFS (HR = 4.71; 95% CI: 3.11-7.15). In conclusion, our findings suggest that patients with RCC and pre-existing T2DM have a shorter OS, increased risk of recurrence, and higher risk for kidney cancer mortality than those without diabetes.


Asunto(s)
Carcinoma de Células Renales/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Neoplasias Renales/mortalidad , Anciano , Carcinoma de Células Renales/complicaciones , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Italia/epidemiología , Neoplasias Renales/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo
18.
Crit Care ; 18(5): 520, 2014 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-25261195

RESUMEN

INTRODUCTION: The pathophysiology of endotoxemia-induced acute kidney injury (AKI) is characterized by an intense activation of the host immune system and renal resident cells by lipopolysaccharide (LPS) and derived proinflammatory products. However, the occurrence of renal fibrosis in this setting has been poorly investigated. The aim of the present study was to investigate the possible association between endothelial dysfunction and acute development of tissue fibrosis in a swine model of LPS-induced AKI. Moreover, we studied the possible effects of coupled plasma filtration adsorption (CPFA) in this setting. METHODS: After 9 hours from LPS infusion and 6 hours of CPFA treatment, histologic and biochemical changes were analyzed in pigs. Apoptosis and endothelial dysfunction were assessed on renal biopsies. The levels of LPS-binding protein (LBP) were quantified with enzyme-linked immunosorbent assay (ELISA). Endothelial cells (ECs) were stimulated in vitro with LPS and cultured in the presence of swine sera and were analyzed with FACS and real-time RT-PCR. RESULTS: In a swine model of LPS-induced AKI, we observed that acute tubulointerstitial fibrosis occurred within 9 hours from LPS injection. Acute fibrosis was associated with dysfunctional alpha-smooth muscle actin (α-SMA)+ ECs characterized by active proliferation (Ki-67+) without apoptosis (caspase-3-). LPS led to EC dysfunction in vitro with significant vimentin and N-cadherin expression and increased collagen I mRNA synthesis. Therapeutic intervention by citrate-based CPFA significantly prevented acute fibrosis in endotoxemic animals, by preserving the EC phenotype in both peritubular capillaries and renal arteries. We found that the removal of LBP from plasma was crucial to eliminate the effects of LPS on EC dysfunction, by blocking LPS-induced collagen I production. CONCLUSIONS: Our data indicate that EC dysfunction might be pivotal in the acute development of tubulointerstitial fibrosis in LPS-induced AKI. Selective removal of the LPS adaptor protein LBP might represent a future therapeutic option to prevent EC dysfunction and tissue fibrosis in endotoxemia-induced AKI.


Asunto(s)
Lesión Renal Aguda/patología , Células Endoteliales/fisiología , Riñón/patología , Lesión Renal Aguda/inducido químicamente , Proteínas de Fase Aguda , Animales , Proteínas Portadoras , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Fibrosis , Riñón/irrigación sanguínea , Riñón/fisiopatología , Glicoproteínas de Membrana , Porcinos
19.
J Nephrol ; 27(5): 555-62, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24574138

RESUMEN

BACKGROUND: Arteriovenous fistula (AVF) stenosis is the major cause of vascular access failure in hemodialysis. Adventitial remodeling has been suggested to play a role in the pathogenesis of AVF stenosis. This study aimed to evaluate adventitial fibrosis in stenotic AVF and investigate the underlying molecular mechanisms. METHODS: Forty-four patients undergoing surgery for AVF creation were examined; ten presented AVF failure, with histological-proven AVF stenosis. RESULTS: In stenotic AVF we observed a significant increase of adventitia extracellular matrix deposition and alpha-smooth muscle actin (α-SMA)(+) cell numbers; most of these cells were myofibroblast (α-SMA(+)/vimentin(+)). Phosphorylated platelet-derived growth factor ß receptor (p-PDGFRß) was significantly increased within the adventitia of stenotic compared to native AVF, along with a marked increase in the phosphorylation of Akt and ERK, two key kinases in PDGFRß signalling. Myofibroblasts were the main cell type associated with the activation of p-PDGFRß. At the same time, we observed a significant adventitial vessels rarefaction in stenotic AVF, as demonstrated by a reduced CD34 expression. This event was associated with a marked reduction in the expression of KDR/fetal liver kinase-1, the main vascular endothelial growth factor receptor. The degree of adventitial fibrosis was directly correlated with the extent of adventitial α-SMA and inversely associated with adventitial CD34 expression. Finally, we observed an increase in CD34(+)/α-SMA(+) cells within the adventitia of failed AVF. CONCLUSION: This study suggests that AVF failure is associated with an increased adventitial fibrosis, myofibroblast activation and capillary rarefaction, potentially linked with endothelial-to-mesenchymal transition. In this scenario, our data suggest that PDGF may play a pathogenic role.


Asunto(s)
Adventicia/patología , Derivación Arteriovenosa Quirúrgica/efectos adversos , Oclusión de Injerto Vascular/patología , Fallo Renal Crónico/terapia , Diálisis Renal , Remodelación Vascular , Venas/patología , Adulto , Adventicia/química , Anciano , Biomarcadores/análisis , Biopsia , Constricción Patológica , Células Endoteliales/química , Células Endoteliales/patología , Femenino , Fibrosis , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Miofibroblastos/química , Miofibroblastos/metabolismo , Estudios Prospectivos , Transducción de Señal , Insuficiencia del Tratamiento , Venas/química
20.
BMC Med Genomics ; 6: 17, 2013 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-23663527

RESUMEN

BACKGROUND: Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome. METHODS: To better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches. RESULTS: Immune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene-Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean±SD of eGFR: 32.27+/-14.7 ml/min) from 17 HD patients (p<0.0001, FDR=5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up-regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean±SD of eGFR: 30.26±14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down-expressed in HD (p=0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p<0.01). CONCLUSION: Taken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets.


Asunto(s)
Perfilación de la Expresión Génica , Fallo Renal Crónico/genética , Insuficiencia Renal Crónica/genética , Adulto , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Receptor 1 de Quimiocinas CX3C , Análisis Discriminante , Regulación hacia Abajo , Femenino , Redes Reguladoras de Genes , Antígenos HLA-G/genética , Antígenos HLA-G/metabolismo , Humanos , Interleucina-15/genética , Interleucina-15/metabolismo , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Quimiocina/metabolismo , Diálisis Renal , Insuficiencia Renal Crónica/inmunología , Insuficiencia Renal Crónica/metabolismo , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Índice de Severidad de la Enfermedad , Regulación hacia Arriba
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