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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803361

RESUMEN

Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [99mTc]Tc-ZHER2:V2 and [99mTc]Tc-ZHER2:2395. [99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 was 25-30 fold lower when compared with [99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with 99mTc using a GGGC chelator. The new probe, [99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.


Asunto(s)
Antineoplásicos Inmunológicos , Riñón , Neoplasias Experimentales , Radiofármacos , Receptor ErbB-2/metabolismo , Tecnecio , Tomografía Computarizada de Emisión de Fotón Único , Animales , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/farmacocinética , Antineoplásicos Inmunológicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Riñón/diagnóstico por imagen , Riñón/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Tecnecio/química , Tecnecio/farmacocinética , Tecnecio/farmacología , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
2.
G Ital Nefrol ; 38(2)2021 Apr 14.
Artículo en Italiano | MEDLINE | ID: mdl-33852219

RESUMEN

The SARS-CoV-2 (Covid-19) has infected about 124 million people worldwide and the total amount of casualties now sits at a staggering 2.7 million. One enigmatic aspect of this disease is the protean nature of the clinical manifestations, ranging from total absence of symptoms to extremely severe cases with multiorgan failure and death. Chronic Kidney Disease (CKD) has emerged as the primary risk factor in the most severe patients, apart from age. Kidney disease and acute kidney injury have been correlated with a higher risk of death. Notably the Italian Society of Nephrology have reported a 10-fold increase in mortality in patients undergoing dialysis compared to the rest of the population, especially during the second phase of the pandemic (26% vs 2.4). These dramatic numbers require an immediate response. At the moment of writing, three Covid-19 vaccines are being administered already , two of which, Pfizer-BioNTech and Moderna, share the same mRNA mechanism and Vaxzevria (AstraZeneca) based on a more traditional approach. All of them are completely safe and reliable. The AIFA scientific commission has suggested that the mRNA vaccines should be administered to older and more fragile patients, while the Vaxzevria (AstraZeneca) vaccine should be reserved for younger subjects above the age of 18. The near future looks bright: there are tens of other vaccines undergoing clinical and preclinical validation, whose preliminary results look promising. The high mortality of CKD and dialysis patients contracting Covid-19 should mandate top priority for their vaccination.


Asunto(s)
/provisión & distribución , Insuficiencia Renal Crónica/complicaciones , Factores de Edad , /etiología , /psicología , Susceptibilidad a Enfermedades/etiología , Miedo , Humanos , Riñón/metabolismo , Diálisis Renal/efectos adversos , Diálisis Renal/mortalidad , Insuficiencia Renal Crónica/mortalidad , Factores de Riesgo , Vacunación
3.
Chin Med J (Engl) ; 134(8): 935-943, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879756

RESUMEN

BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.


Asunto(s)
/metabolismo , Riñón/metabolismo , Análisis de la Célula Individual , Vejiga Urinaria/metabolismo , Expresión Génica , Humanos , Análisis de Secuencia de ARN
4.
Georgian Med News ; (311): 156-162, 2021 Feb.
Artículo en Ruso | MEDLINE | ID: mdl-33814411

RESUMEN

Objective - to find out the possibility of using molecular hydrogen in the correction of no-reflow syndrome in the polyuric stage of acute kidney injury 72 hours after the administration of mercuric chloride in rats on a hyposodium diet. The experiments were performed on 60 male white non-linear sexually mature rats weighing 0.16-0.18 kg to study the effect of water loading with saturation with molecular hydrogen. Sublimate nephropathy was modeled under conditions of a hyposodium diet by subcutaneous injection of 0.1% mercury dichloride solution at a dosage of 5 mg/kg with a study after 72 hours, which corresponded to the early polyuric stage of acute kidney injury and the development of no-reflow syndrome. To saturate the water with molecular hydrogen at a concentration of 1.2 ppm and a redox potential from -100 to -350 mV, a new generation H2 generator Blue Water 900 (Korea) was used, containing an improved proton-exchange membrane PEM/SPE. Used: pathophysiological, biochemical, functional, chemiluminescent, statistical research methods. The antioxidant effect of loading with water with saturation with molecular hydrogen leads to a decrease in the loss of sodium ions due to an improvement in its reabsorption and ß2-microglobulin in the proximal tubule, a decrease in lipid peroxidation in the renal cortex was noted, the degree of its damage by an increase in the K+/Na+ ratio and a decrease in degree of edema. Improvement in the condition of the proximal nephron led to an increase in total, enzymatic fibrinolytic activity in the renal cortex. The increase in the activity of succinate dehydrogenase in the renal cortex is due to an increase in the delivery of electrons due to the negative redox potential and the selective antioxidant effect of molecular hydrogen. The anti-edema effect of molecular hydrogen was revealed at the level of 7 layers of the kidney. During the formation of the no-reflow syndrome in rats on a low-sodium diet 72 hours after the introduction of mercuric chloride, the possibility of breaking large and small vicious circles with an antioxidant solution of H2 was shown due to its high permeability and the ability to neutralize the hydroxyl radical and peroxynitrite.


Asunto(s)
Lesión Renal Aguda , Cloruro de Mercurio , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Animales , Hidrógeno/metabolismo , Riñón/metabolismo , Peroxidación de Lípido , Masculino , Ratas
5.
Zhonghua Yi Xue Za Zhi ; 101(14): 1036-1040, 2021 Apr 13.
Artículo en Chino | MEDLINE | ID: mdl-33845544

RESUMEN

Objective: To investigate the effects of normobaric hyperoxia intervention on renal ischemia-reperfusion injury in rats and its possible mechanism. Methods: Twenty-one adult male SD rats were enrolled and their right kidneys were excised. After two weeks, they were randomly assigned to 3 groups, with 7 rats in each group, namely sham-operated group (Group S), ischemia-reperfusion group (Group I/R), and normobaric hyperoxia+ischemia-reperfusion group (Group NBHO+I/R). In group S, only the left renal pedicle was isolated, but no ischemic treatment was performed. However, in group I/R and group NBHO+I/R, left renal pedicles were separated and left renal ischemia was induced by noninvasive arterial clamp for 45 min, and after 24 h of reperfusion, rats in group S and group I/R inhaled regular concentration of oxygen (21%), while rats in group NBHO+I/R inhaled high concentration of oxygen (60%), 2 h at each time, once a day for 7 days. On the 7th day after surgery, blood urea nitrogen (BUN) and creatinine (Cr) levels were measured by taking blood from the orbital veins of rats. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) was detected from the left kidney tissues. The mRNA and protein contents of Keap1 and Nrf2 gene in kidney tissues were determined by qPCR and Western Blotting, respectively. Hematoxylin-eosin staining (HE) was employed to observe the pathological changes of kidney tissue. Immunohistochemical staining was used to measure the protein expression of Keap1 and Nrf2 in kidney tissues. Results: Compared with group S, the serum BUN [(10.7±1.7) mmol/L, (8.4±1.0) mmol/L vs (6.1±1.3) mmol/L, both P<0.05] and Cr [(81.0±3.7) µmol/L, (62.9±3.4) µmol/L vs (48.3±2.9) µmol/L, both P<0.05] levels of rats in the group I/R and group NBHO+I/R increased, and the I/R group had the most significant increase. Compared with group S, the MDA content of kidney tissue in the rats of group I/R and NBHO+I/R increased [(10.5±1.0) µmol/L, (8.6±0.8) µmol/L vs (6.5±0.5) µmol/L, both P<0.05], but the MDA content in group NBHO+I/R was lower than that of group I/R (P<0.05). Compared with group S, the SOD content in the kidney tissues of rats in both group I/R and group NBHO+I/R decreased. However, the SOD content of group NBHO+I/R was higher than that of group I/R (P<0.05). Compared with group S, the mRNA and protein contents of Keap1 gene in kidney tissues of group I/R and group NBHO+I/R decreased, and group NBHO+I/R had the most significant decrease (P<0.05). However, compared with group S, mRNA and protein expressions of Nrf2 gene increased in kidney tissues of group I/R and group NBHO+I/R, and NBHO+I/R group had the most significant increase (P<0.05). Postoperative pathological results suggested that compared with group S, the pathological damage of kidney tissues in group I/R and group NBHO+I/R increased, but the degree of damage in group NBHO+I/R was lower than that in group I/R. Conclusion: Normobaric hyperoxia intervention may have protective effects on renal ischemia-reperfusion injury in rats by activating Keap1-Nrf2 signaling pathway.


Asunto(s)
Hiperoxia , Daño por Reperfusión , Animales , Proteína 1 Asociada A ECH Tipo Kelch , Riñón/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/terapia
6.
Nat Commun ; 12(1): 2190, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33850129

RESUMEN

The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity. We performed single nucleus ATAC (snATAC-seq) and RNA (snRNA-seq) sequencing to generate paired, cell-type-specific chromatin accessibility and transcriptional profiles of the adult human kidney. We demonstrate that snATAC-seq is comparable to snRNA-seq in the assignment of cell identity and can further refine our understanding of functional heterogeneity in the nephron. The majority of differentially accessible chromatin regions are localized to promoters and a significant proportion are closely associated with differentially expressed genes. Cell-type-specific enrichment of transcription factor binding motifs implicates the activation of NF-κB that promotes VCAM1 expression and drives transition between a subpopulation of proximal tubule epithelial cells. Our multi-omics approach improves the ability to detect unique cell states within the kidney and redefines cellular heterogeneity in the proximal tubule and thick ascending limb.


Asunto(s)
Cromatina/genética , Heterogeneidad Genética , Riñón/metabolismo , Transcriptoma , Adulto , Regulación de la Expresión Génica , Factor Nuclear 4 del Hepatocito , Humanos , Persona de Mediana Edad , FN-kappa B , Regiones Promotoras Genéticas , ARN Nuclear Pequeño , Factor de Transcripción AP-2 , Factores de Transcripción/metabolismo , Transposasas , Molécula 1 de Adhesión Celular Vascular
7.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800423

RESUMEN

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.


Asunto(s)
Anestésicos por Inhalación/uso terapéutico , Isoflurano/uso terapéutico , Trasplante de Riñón , Riñón/metabolismo , Daño por Reperfusión/prevención & control , Sevoflurano/uso terapéutico , Animales , Humanos
8.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801911

RESUMEN

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-ß-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Neoplasias de la Mama/tratamiento farmacológico , Inflamación/prevención & control , Enfermedades Renales/prevención & control , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacocinética , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cisplatino , Femenino , Humanos , Inflamación/metabolismo , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Masculino , Ratones Desnudos , Ratas Endogámicas WKY , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
9.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800916

RESUMEN

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin-angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.


Asunto(s)
Antibacterianos/toxicidad , Fructosa/toxicidad , Microbioma Gastrointestinal/fisiología , Hipertensión/microbiología , Minociclina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Animales , Antibacterianos/administración & dosificación , Ácidos Grasos Volátiles/metabolismo , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/aislamiento & purificación , Bacterias Gramnegativas/metabolismo , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Bacterias Grampositivas/metabolismo , Hipertensión/etiología , Riñón/efectos de los fármacos , Riñón/metabolismo , Lactancia , Masculino , Minociclina/administración & dosificación , Óxido Nítrico/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Sistema Renina-Angiotensina/fisiología
10.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669690

RESUMEN

The 129sv mouse strain is particularly sensitive to experimental immune-mediated nephritis. Previous studies have indicated that transforming growth factor-ß (TGF-ß) plays a critical role in both immune modulation and tissue fibrogenesis in various diseases and that its biological activities are exerted via the SMAD family. In this study, we aimed to determine whether TGF-ß/SMAD signaling is essential for the development of immune-mediated nephritis in 129sv mice. Relative to C57BL/6J control mice with anti-glomeruli basement membrane (GBM) nephritis, 129sv mice with anti-GBM nephritis exhibited increased renal collagen deposition. Additionally, higher mRNA levels of pro-collagen and collagen IV, higher serum levels of active and total TGF-ß1, and increased TGF-ß1, TGF-ßIIR, and phosphorylated SMAD expression were detected in these mice. Deletion of Smad3 in 129sv mice ameliorated anti-GBM induced nephritis, including crescentic glomerulonephritis. Collectively, these findings indicate that the heightened experimental nephritis and fibrotic disease in the 129sv strain of mice are regulated by SMAD3, which could be a potential therapeutic target for immune-mediated nephritis.


Asunto(s)
Glomerulonefritis Membranoproliferativa/metabolismo , Glomerulonefritis Membranoproliferativa/patología , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Colágeno/genética , Colágeno/metabolismo , Regulación de la Expresión Génica , Glomerulonefritis Membranoproliferativa/sangre , Glomerulonefritis Membranoproliferativa/genética , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/sangre
11.
Nat Commun ; 12(1): 1745, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741971

RESUMEN

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.


Asunto(s)
Cistationina gamma-Liasa/química , Cistationina gamma-Liasa/metabolismo , Dieta , Proteínas/química , Proteínas/metabolismo , Envejecimiento/metabolismo , Animales , Encéfalo/metabolismo , Cistationina gamma-Liasa/genética , Sulfuro de Hidrógeno/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculos/metabolismo , Proteínas/genética , Transcriptoma
12.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671448

RESUMEN

Ultrasound imaging is a widely used, readily accessible and safe imaging modality. Molecularly-targeted microbubble- and nanobubble-based contrast agents used in conjunction with ultrasound imaging expand the utility of this modality by specifically targeting and detecting biomarkers associated with different pathologies including cancer. In this study, nanobubbles directed to a cancer biomarker derived from the Receptor Protein Tyrosine Phosphatase mu, PTPmu, were evaluated alongside non-targeted nanobubbles using contrast enhanced ultrasound both in vitro and in vivo in mice. In vitro resonant mass and clinical ultrasound measurements showed gas-core, lipid-shelled nanobubbles conjugated to either a PTPmu-directed peptide or a Scrambled control peptide were equivalent. Mice with heterotopic human tumors expressing the PTPmu-biomarker were injected with PTPmu-targeted or control nanobubbles and dynamic contrast-enhanced ultrasound was performed. Tumor enhancement was more rapid and greater with PTPmu-targeted nanobubbles compared to the non-targeted control nanobubbles. Peak tumor enhancement by the PTPmu-targeted nanobubbles occurred within five minutes of contrast injection and was more than 35% higher than the Scrambled nanobubble signal for the subsequent two minutes. At later time points, the signal in tumors remained higher with PTPmu-targeted nanobubbles demonstrating that PTPmu-targeted nanobubbles recognize tumors using molecular ultrasound imaging and may be useful for diagnostic and therapeutic purposes.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Medios de Contraste/química , Imagen Molecular , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Ultrasonografía , Animales , Células Endoteliales/metabolismo , Femenino , Humanos , Riñón/metabolismo , Riñón/patología , Ratones Desnudos , Neoplasias/patología
13.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669022

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. METHODS: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6-/- MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. RESULTS: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. CONCLUSION: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.


Asunto(s)
Endotelio Vascular/metabolismo , Interleucina-6/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Linfocitos T/inmunología , Acetilcolina/farmacología , Animales , Aorta/inmunología , Aorta/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/genética , Riñón/metabolismo , Riñón/patología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
14.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669059

RESUMEN

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.


Asunto(s)
Hipertensión/metabolismo , Enfermedades Renales/metabolismo , Riñón/crecimiento & desarrollo , Nefronas/crecimiento & desarrollo , Sistema Renina-Angiotensina , Renina/metabolismo , Adulto , Animales , Modelos Animales de Enfermedad , Disbiosis/metabolismo , Epigénesis Genética , Humanos , Hipertensión/genética , Riñón/metabolismo , Enfermedades Renales/enzimología , Enfermedades Renales/genética , Nefronas/citología , Nefronas/metabolismo , Óxido Nítrico/deficiencia , Óxido Nítrico/metabolismo , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiología
15.
Kidney Blood Press Res ; 46(2): 245-249, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33756485

RESUMEN

BACKGROUND: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. METHODS: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. RESULTS: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. CONCLUSIONS: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.


Asunto(s)
Aloinjertos/efectos de los fármacos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Expresión Génica/efectos de los fármacos , Riñón/efectos de los fármacos , Adulto , Anciano , Aloinjertos/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , /antagonistas & inhibidores , Antihipertensivos/farmacología , /genética , Femenino , Humanos , Riñón/metabolismo , Trasplante de Riñón , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , ARN Mensajero/genética , Sistema Renina-Angiotensina/efectos de los fármacos
16.
Sci Rep ; 11(1): 7132, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33785846

RESUMEN

The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 µg/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases.


Asunto(s)
Antivirales/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Ivermectina/farmacología , Animales , Antivirales/administración & dosificación , Peso Corporal/efectos de los fármacos , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Modelos Animales de Enfermedad , Femenino , Ivermectina/administración & dosificación , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/virología , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Virus de la Hepatitis Murina/patogenicidad , Neutrófilos/efectos de los fármacos , Proteínas/metabolismo , Transaminasas/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Carga Viral/efectos de los fármacos
17.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670516

RESUMEN

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney's filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1's role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.


Asunto(s)
Lesión Renal Aguda/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hemo/metabolismo , Enfermedades Renales/metabolismo , Estrés Oxidativo , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/patología , Animales , Humanos , Riñón/citología , Riñón/enzimología , Riñón/metabolismo , Enfermedades Renales/enzimología , Enfermedades Renales/patología , Túbulos Renales/citología , Túbulos Renales/enzimología , Túbulos Renales/metabolismo , Sustancias Protectoras/metabolismo
18.
Mol Med Rep ; 23(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33655337

RESUMEN

Heat stroke can induce a systemic inflammatory response, which may lead to multi­organ dysfunction including acute kidney injury (AKI) and electrolyte disturbances. To investigate the pathogenesis of heat stroke (HS)­related AKI, a mouse model of HS was induced by increasing the animal's core temperature to 41˚C. Blood samples obtained from the tail vein were used to measure plasma glucose and creatinine levels. Micro­positron emission tomography­computed tomography (micro­PET/CT), H&E staining and transmission electron microscopy were conducted to examine metabolic and morphological changes in the mouse kidneys. Immunohistochemistry (IHC) and western blot analyses were performed to investigate the expression of apoptosis­inducing factor mitochondria­associated 2 (Aifm2), high­mobility group box 1 (HMGB1) and receptor for advanced glycosylation end products (RAGE). Liquid chromatography­mass spectrometry analysis was conducted to find differential metabolites and signaling pathways. The HS mouse model was built successfully, with significantly increased creatinine levels detected in the serum of HS mice compared with controls, whereas micro­PET/CT revealed active metabolism in the whole body of HS mice. H&E and TUNEL staining revealed that the kidneys of HS mice exhibited signs of hemorrhage and apoptosis. IHC and western blotting demonstrated significant upregulation of Aifm2, HMGB1 and RAGE in response to HS. Finally, 136 differential metabolites were screened out, and enrichment of the 'biosynthesis of unsaturated fatty acids' pathway was detected. HS­associated AKI is the renal manifestation of systemic inflammatory response syndrome, and may be triggered by the HMGB1/RAGE pathway. Metabolomics indicated increased adrenic acid, docosahexaenoic acid and eicosapentaenoic acid may serve as metabolic biomarkers for AKI in HS. The findings suggested that a correlation between the HMGB1/RAGE pathway and biosynthesis of unsaturated fatty acids may contribute to the progression of HS­related AKI.


Asunto(s)
Lesión Renal Aguda/sangre , Proteínas Reguladoras de la Apoptosis/sangre , Proteína HMGB1/sangre , Golpe de Calor/sangre , Oxidorreductasas/sangre , Receptor para Productos Finales de Glicación Avanzada/sangre , Lesión Renal Aguda/diagnóstico por imagen , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Golpe de Calor/complicaciones , Golpe de Calor/diagnóstico por imagen , Golpe de Calor/patología , Humanos , Riñón/metabolismo , Riñón/patología , Metabolómica , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Transducción de Señal/genética
19.
Am J Physiol Renal Physiol ; 320(3): F485-F491, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33522411

RESUMEN

Extracellular proteases can activate the epithelial Na channel (ENaC) by cleavage of the γ subunit. Here, we investigated the cleavage state of the channel in the kidneys of mice and rats on a low-salt diet. We identified the cleaved species of channels expressed in Fisher rat thyroid cells by coexpressing the apical membrane-bound protease channel-activating protease 1 (CAP1; prostasin). To compare the peptides produced in the heterologous system with those in the mouse kidney, we treated both lysates with PNGaseF to remove N-linked glycosylation. The apparent molecular mass of the smallest COOH-terminal fragment of γENaC (52 kDa) was indistinguishable from that of the CAP1-induced species in Fisher rat thyroid cells. Similar cleaved peptides were observed in total and cell surface fractions of the rat kidney. This outcome suggests that most of the subunits at the surface have been processed by extracellular proteases. This was confirmed using nonreducing gels, in which the NH2- and COOH-terminal fragments of γENaC are linked by a disulfide bond. Under these conditions, the major cleaved form in the rat kidney had an apparent molecular mass of 56 kDa, ∼4 kDa lower than that of the full-length form, consistent with excision of a short peptide by two proteolytic events. We conclude that the most abundant γENaC species in the apical membrane of rat and mouse kidneys on a low-Na diet is the twice-cleaved, presumably activated form.NEW & NOTEWORTHY We have identified the major aldosterone-dependent cleaved form of the epithelial Na channel (ENaC) γ subunit in the kidney as a twice-cleaved peptide. This form appears to be identical in size with a subunit cleaved in vitro by the extracellular protease channel-activating protease 1 (prostasin). In the absence of reducing agents, it has an overall molecular mass less than that of the intact subunit, consistent with the excision of an inhibitory domain.


Asunto(s)
Canales Epiteliales de Sodio/metabolismo , Riñón/metabolismo , Serina Endopeptidasas/metabolismo , Sodio/metabolismo , Aldosterona/metabolismo , Animales , Dieta Hiposódica/métodos , Ratones , Subunidades de Proteína/metabolismo , Proteolisis , Ratas
20.
Am J Physiol Renal Physiol ; 320(3): F505-F517, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33522410

RESUMEN

Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8+ T cells, resident macrophages (CD11bhiF4/80loLy6C-), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8+ T cells, Ly6C- macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/farmacología , Macrófagos/metabolismo , Angiotensina II/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones
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