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1.
Curr Top Membr ; 93: 1-25, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39181576

RESUMO

Mammalian cell membranes are very dynamic where they respond to several environmental stimuli by rearranging the membrane composition by basic biological processes, including endocytosis. In this context, receptor-mediated endocytosis, either clathrin-dependent or caveolae-dependent, is involved in different physiological and pathological conditions. In the last years, an important amount of evidence has been reported that kidney function involves the modulation of different types of endocytosis, including renal protein handling. In addition, the dysfunction of the endocytic machinery is involved with the development of proteinuria as well as glomerular and tubular injuries observed in kidney diseases associated with hypertension, diabetes, and others. In this present review, we will discuss the mechanisms underlying the receptor-mediated endocytosis in different glomerular cells and proximal tubule epithelial cells as well as their modulation by different factors during physiological and pathological conditions. These findings could help to expand the current understanding regarding renal protein handling as well as identify possible new therapeutic targets to halt the progression of kidney disease.


Assuntos
Endocitose , Humanos , Animais , Nefropatias/metabolismo , Nefropatias/patologia , Rim/metabolismo , Rim/patologia , Receptores de Superfície Celular/metabolismo
2.
Curr Issues Mol Biol ; 44(3): 998-1011, 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35723289

RESUMO

Kidney proximal tubules are a key segment in the reabsorption of solutes and water from the glomerular ultrafiltrate, an essential process for maintaining homeostasis in body fluid compartments. The abundant content of Na+ in the extracellular fluid determines its importance in the regulation of extracellular fluid volume, which is particularly important for different physiological processes including blood pressure control. Basolateral membranes of proximal tubule cells have the classic Na+ + K+-ATPase and the ouabain-insensitive, K+-insensitive, and furosemide-sensitive Na+-ATPase, which participate in the active Na+ reabsorption. Here, we show that nanomolar concentrations of ceramide-1 phosphate (C1P), a bioactive sphingolipid derived in biological membranes from different metabolic pathways, promotes a strong inhibitory effect on the Na+-ATPase activity (C1P50 ≈ 10 nM), leading to a 72% inhibition of the second sodium pump in the basolateral membranes. Ceramide-1-phosphate directly modulates protein kinase A and protein kinase C, which are known to be involved in the modulation of ion transporters including the renal Na+-ATPase. Conversely, we did not observe any effect on the Na+ + K+-ATPase even at a broad C1P concentration range. The significant effect of ceramide-1-phosphate revealed a new potent physiological and pathophysiological modulator for the Na+-ATPase, participating in the regulatory network involving glycero- and sphingolipids present in the basolateral membranes of kidney tubule cells.

3.
Int J Mol Sci ; 23(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36232558

RESUMO

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.


Assuntos
Acetilglucosamina , N-Acetilglucosaminiltransferases , Acetilglucosamina/metabolismo , Hexosaminas/metabolismo , Homeostase , Rim/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional
4.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430671

RESUMO

Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.


Assuntos
Injúria Renal Aguda , COVID-19 , Insuficiência Renal Crônica , Humanos , COVID-19/complicações , SARS-CoV-2 , Injúria Renal Aguda/metabolismo , Insuficiência Renal Crônica/metabolismo , Túbulos Renais Proximais/metabolismo
5.
Int J Mol Sci ; 23(2)2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35055044

RESUMO

Renal proximal tubule cells (PTECs) act as urine gatekeepers, constantly and efficiently avoiding urinary protein waste through receptor-mediated endocytosis. Despite its importance, little is known about how this process is modulated in physiologic conditions. Data suggest that the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway regulates PTEC protein reabsorption. Here, we worked on the hypothesis that the physiologic albumin concentration and PI3K/AKT pathway form a positive feedback loop to expand endocytic capacity. Using LLC-PK1 cells, a model of PTECs, we showed that the PI3K/AKT pathway is required for megalin recycling and surface expression, affecting albumin uptake. Inhibition of this pathway stalls megalin at EEA1+ endosomes. Physiologic albumin concentration (0.01 mg/mL) activated AKT; this depends on megalin-mediated albumin endocytosis and requires previous activation of PI3K/mTORC2. This effect is correlated to the increase in albumin endocytosis, a phenomenon that we refer to as "albumin-induced albumin endocytosis". Mice treated with L-lysine present decreased albumin endocytosis leading to proteinuria and albuminuria associated with inhibition of AKT activity. Renal cortex explants obtained from control mice treated with MK-2206 decreased albumin uptake and promoted megalin internalization. Our data highlight the mechanism behind the capacity of PTECs to adapt albumin reabsorption to physiologic fluctuations in its filtration, avoiding urinary excretion.


Assuntos
Células Epiteliais/metabolismo , Retroalimentação Fisiológica , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Albuminas/metabolismo , Animais , Biomarcadores , Endocitose , Células Epiteliais/efeitos dos fármacos , Imunofluorescência , Expressão Gênica , Túbulos Renais Proximais/citologia , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Transporte Proteico , Transdução de Sinais/efeitos dos fármacos
6.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769064

RESUMO

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor ß (TGFß), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1ß (IL-1ß) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Aspirina/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Glomérulos Renais/efeitos dos fármacos , Sepse/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Albuminas/farmacologia , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Testes de Função Renal/métodos , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteinúria/induzido quimicamente , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , RNA Mensageiro/metabolismo , Sepse/metabolismo
7.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L596-L602, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783619

RESUMO

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Humanos , Hipertensão/mortalidade , Pandemias , Pneumonia Viral/mortalidade , Fatores de Risco , SARS-CoV-2
8.
J Biol Chem ; 293(29): 11388-11400, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29871929

RESUMO

The role of albumin reabsorption in proximal tubule (PT) cells has emerged as an important factor in the genesis of albuminuria observed in the early stages of diabetes. Evidence has shown that a decrease in megalin expression could be the key mechanism in this process. In the present work, we investigated the molecular mechanism underlying the modulation of albumin endocytosis in LLC-PK1 cells, a model of PT cells. High glucose concentrations (HG) inhibited megalin expression and albumin endocytosis after 48 h of incubation. This inhibitory effect involves the entrance of glucose into PT cells through SGLT located at the luminal membrane. Once inside PT cells, glucose is diverted to the hexosamine biosynthetic pathway (HBP) increasing O-GlcNAcylation of several intracellular proteins, including PKB. This process promotes the inhibition of PKB activity measured by its phosphorylation at Thr-308 and Ser-473 and phosphorylation of specific substrates, glycogen synthase kinase 3ß (GSK3ß) and tuberous sclerosis complex 2. The decrease in PKB activity led to a decrease in megalin expression and, consequently, reducing albumin endocytosis in LLC-PK1 cells. HG did not change mammalian target of rapamycin (mTOR) C2 activity, responsible for phosphorylated PKB at Ser-473. In addition, HG activated the mTORC1/S6K pathway, but this effect was not correlated to the decrease in megalin expression or albumin endocytosis. Taken together, our data help to clarify the current understanding underlying the genesis of tubular albuminuria induced by hyperglycemia in the early stage of diabetes pathogenesis.


Assuntos
Endocitose , Hiperglicemia/metabolismo , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Soroalbumina Bovina/metabolismo , Acilação , Animais , Bovinos , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Glucose/metabolismo , Túbulos Renais Proximais/citologia , Sus scrofa
9.
J Biol Chem ; 293(33): 12749-12758, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29954945

RESUMO

Hypertensive individuals are at greater risk for developing chronic kidney disease (CKD). Reducing proteinuria has been suggested as a possible therapeutic approach to treat CKD. However, the mechanisms underlying the development of proteinuria in hypertensive conditions are incompletely understood. Cardiac and vascular dysfunction is associated with changes in the O-GlcNAcylation pathway in hypertensive models. We hypothesized that O-GlcNAcylation is also involved in renal damage, especially development of proteinuria, associated with hypertension. Using the spontaneously hypertensive rat (SHR) model, we observed higher renal cortex O-GlcNAcylation, glutamine-fructose aminotransferase (GFAT), and O-GlcNAc transferase (OGT) protein expression, which positively correlated with proteinuria. Interestingly, this was observed in hypertensive, but not pre-hypertensive, rats. Pharmacological inhibition of GFAT decreased renal cortex O-GlcNAcylation, proteinuria, and albuminuria in SHR. Using a proximal tubule cell line, we observed that increased O-GlcNAcylation reduced megalin surface expression and albumin endocytosis in vitro, and the effects were correlated in vivo Moreover, megalin is O-GlcNAcylated both in vitro and in vivo In conclusion, our results demonstrate a new mechanism involved in hypertension-associated proteinuria.


Assuntos
Acetilglucosamina/química , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/metabolismo , Hipertensão/fisiopatologia , Túbulos Renais Proximais/patologia , Proteinúria/etiologia , Reabsorção Renal , Animais , Células Cultivadas , Endocitose , Glicosilação , Túbulos Renais Proximais/metabolismo , Masculino , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Proteinúria/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Suínos
10.
Arch Biochem Biophys ; 674: 108115, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31560867

RESUMO

Evidence points to a possible role of tubular sodium reabsorption in worsening renal injury. Proximal tubule (PT) albumin overload is a critical process in the development of tubule-interstitial injury (TII), and consequently in progression of renal disease. We studied the possible correlation between changes in albumin concentration in the lumen of PT with modification of Na+-ATPase activity. An albumin overload animal model and LLC-PK1 cells as a model of PT cells were used. Albumin overload was induced by intraperitoneal injection of BSA in 14-week-old male Wistar rats. An increase in sodium clearance, fractional excretion of sodium, proteinuria, ratio between urinary protein and creatinine, and albuminuria were observed. These observations indicate that there could be a correlation between an increase in albumin in the lumen of PTs and renal sodium excretion. We observed that the activity of both Na+-ATPase and (Na++K+)ATPase decreased in the renal cortex of an albumin overload animal model. Using LLC-PK1 cells as a model of PT cells, inhibition of Na+-ATPase activity was observed with higher albumin concentrations, similar to that observed in the animal model. The inhibition of protein kinase B by higher albumin concentration was found to be a critical step in the inhibition of Na+-ATPase activity. Interestingly, activation of the ERK1/2/mTORC1/S6K pathway was required for protein kinase B inhibition. This mechanism leads to a decrease in protein kinase C activity and, consequently to inhibition of Na+-ATPase activity. Taken together, our results indicate that the molecular mechanism underlying the modulation of PT Na+-ATPase activity by albumin overload involves activation of the ERK1/2/mTORC1/S6K pathway, which leads to inhibition of the mTORC2/PKB/PKC pathway. Our findings contribute to better understanding regarding handing of renal Na+ induced by albumin overload in the lumen of PTs and, consequently, in the progression of renal disease.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Túbulos Renais Proximais/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Bovinos , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ratos Wistar , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Suínos
11.
Biochim Biophys Acta ; 1860(7): 1431-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27102282

RESUMO

BACKGROUND: The natriuretic effect of uroguanylin (UGN) involves reduction of proximal tubule (PT) sodium reabsorption. However, the target sodium transporters as well as the molecular mechanisms involved in these processes remain poorly understood. METHODS: To address the effects of UGN on PT (Na(+)+K(+))ATPase and the signal transduction pathways involved in this effect, we used LLC-PK1 cells. The effects of UGN were determined through ouabain-sensitive ATP hydrolysis and immunoblotting assays during different experimental conditions. RESULTS: We observed that UGN triggers cGMP/PKG and cAMP/PKA pathways in a sequential way. The activation of PKA leads to the inhibition of mTORC2 activity, PKB phosphorylation at S473, PKB activity and, consequently, a decrease in the mTORC1/S6K pathway. The final effects are decreased expression of the α1 subunit of (Na(+)+K(+))ATPase and inhibition of enzyme activity. CONCLUSIONS: These results suggest that the molecular mechanism of action of UGN on sodium reabsorption in PT cells is more complex than previously thought. We propose that PKG-dependent activation of PKA leads to the inhibition of the mTORC2/PKB/mTORC1/S6K pathway, an important signaling pathway involved in the maintenance of the PT sodium pump expression and activity. GENERAL SIGNIFICANCE: The current results expand our understanding of the signal transduction pathways involved in the overall effect of UGN on renal sodium excretion.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Natriuréticos/farmacologia , Peptídeos Natriuréticos/farmacologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Ativação Enzimática , Hidrólise , Túbulos Renais Proximais/enzimologia , Células LLC-PK1 , Natriurese/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Eliminação Renal/efeitos dos fármacos , Reabsorção Renal/efeitos dos fármacos , Sódio/metabolismo , Suínos , Serina-Treonina Quinases TOR/antagonistas & inibidores
12.
Biochim Biophys Acta ; 1860(11 Pt A): 2438-2444, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27431603

RESUMO

BACKGROUND: The molecular mechanisms involved in erythrocyte invasion by malaria parasite are well understood, but the contribution of host components is not. We recently reported that Ang-(1-7) impairs the erythrocytic cycle of P. falciparum through Mas receptor-mediated reduction of protein kinase A (PKA) activity. The effects of bradykinin (BK), a peptide of the kallikrein-kinin system (KKS), can be potentiated by Ang-(1-7), or angiotensin-converting enzyme (ACE) inhibitors, such as captopril. We investigated the coordinated action between renin-angiotensin system (RAS) and KKS peptides in the erythrocyte invasion by P. falciparum. METHODS: We used human erythrocytes infected with P. falciparum to assess the influence of RAS and KKS peptides in the invasion of new erythrocytes. RESULTS: The inhibitory effects of Ang-(1-7) were mimicked by captopril. 10(-8)M BK decreased new ring forms and this effect was sensitive to 10(-8)M HOE-140 and 10(-7)M A779, B2 and Mas receptor antagonists, respectively. However, DALBK, a B1 receptor blocker, had no effect. The inhibitory effect of Ang-(1-7) was reversed by HOE-140 and A779 at the same concentrations. Co-immunoprecipitation assay revealed an association between B2 and Mas receptors. BK also inhibited PKA activity, which was sensitive to both HOE-140 and A779. CONCLUSIONS: The results suggest that B2 and Mas receptors are mediators of Ang-(1-7) and BK inhibitory effects, through a cross-signaling pathway, possibly by the formation of a heterodimer. GENERAL SIGNIFICANCE: Our results describe new elements in host signaling that could be involved in parasite invasion during the erythrocyte cycle of P. falciparum.


Assuntos
Eritrócitos/parasitologia , Plasmodium falciparum/patogenicidade , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Protozoários/metabolismo , Receptor B2 da Bradicinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Cultivadas , Humanos , Plasmodium falciparum/metabolismo , Ligação Proteica , Proto-Oncogene Mas
13.
J Biol Chem ; 289(24): 16790-801, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24790108

RESUMO

High albumin concentrations in the proximal tubule of the kidney causes tubulointerstitial injury, but how this process occurs is not completely known. To address the signal transduction pathways mis-regulated in renal injury, we studied the modulation of mammalian target of rapamycin (mTOR) complexes by physiologic and pathophysiologic albumin concentrations in proximal tubule cells. Physiologic albumin concentrations activated the PI3K/mTORC2/PKB/mTORC1/S6 kinase (S6K) pathway, but pathophysiologically high albumin concentrations overactivated mTORC1 and inhibited mTORC2 activity. This control process involved the activation of ERK1/2, which promoted the inhibition of TSC2 and activation of S6K. Furthermore, S6K was crucial to promoting the over activation of mTORC1 and inhibition of mTORC2. Megalin expression at the luminal membrane is reduced by high concentrations of albumin. In addition, knockdown of megalin mimicked all the effects of pathophysiologic albumin concentrations, which disrupt normal signal transduction pathways and lead to an overactivation of mTORC1 and inhibition of mTORC2. These data provide new perspectives for understanding the molecular mechanisms behind the effects of albumin on the progression of renal disease.


Assuntos
Albuminúria/metabolismo , Túbulos Renais Proximais/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Albuminas/farmacologia , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Túbulos Renais Proximais/citologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Complexos Multiproteicos/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Suínos , Serina-Treonina Quinases TOR/genética
14.
Brain Res ; 1822: 148669, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37951562

RESUMO

Cerebral malaria (CM) pathogenesis is described as a multistep mechanism. In this context, monocytes have been implicated in CM pathogenesis by increasing the sequestration of infected red blood cells to the brain microvasculature. In disease, endothelial activation is followed by reduced monocyte rolling and increased adhesion. Nowadays, an important challenge is to identify potential pro-inflammatory stimuli that can modulate monocytes behavior. Our group have demonstrated that bradykinin (BK), a pro-inflammatory peptide involved in CM, is generated during the erythrocytic cycle of P. falciparum and is detected in culture supernatant (conditioned medium). Herein we investigated the role of BK in the adhesion of monocytes to endothelial cells of blood brain barrier (BBB). To address this issue human monocytic cell line (THP-1) and human brain microvascular endothelial cells (hBMECs) were used. It was observed that 20% conditioned medium from P. falciparum infected erythrocytes (Pf-iRBC sup) increased the adhesion of THP-1 cells to hBMECs. This effect was mediated by BK through the activation of B2 and B1 receptors and involves the increase in ICAM-1 expression in THP-1 cells. Additionally, it was observed that angiotensin-converting enzyme (ACE) inhibitor, captopril, enhanced the effect of both BK and Pf-iRBC sup on THP-1 adhesion. Together these data show that BK, generated during the erythrocytic cycle of P. falciparum, could play an important role in adhesion of monocytes in endothelial cells lining the BBB.


Assuntos
Barreira Hematoencefálica , Bradicinina , Adesão Celular , Malária Cerebral , Malária Falciparum , Plasmodium falciparum , Humanos , Bradicinina/metabolismo , Adesão Celular/fisiologia , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Eritrócitos/parasitologia , Malária Cerebral/metabolismo , Malária Cerebral/parasitologia , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Monócitos/fisiologia , Plasmodium falciparum/fisiologia , Barreira Hematoencefálica/fisiopatologia
15.
Intensive Care Med Exp ; 12(1): 81, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39298036

RESUMO

This narrative review delves into the intricate interplay between the lungs and the kidneys, with a focus on elucidating the pathogenesis of diseases influenced by immunological factors, acid-base regulation, and blood gas disturbances, as well as assessing the effects of various therapeutic modalities on these interactions. Key disorders, such as anti-glomerular basement membrane (anti-GBM) disease, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and Anti-neutrophil Cytoplasmic Antibodies (ANCA) associated vasculitis (AAV), are also examined to shed light on their underlying mechanisms. This review also explores the relationship between acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), emphasizing how inflammatory mediators can lead to systemic damage and impact multiple organs. In ARDS, fluid overload exacerbates pulmonary edema, while imbalances in blood volume, such as hypovolemia or hypervolemia, can precipitate renal dysfunction. The review highlights how mechanical ventilation strategies can compromise renal blood flow, trigger systemic inflammation, and induce hemodynamic and neurohormonal alterations, all contributing to lung and kidney damage. The impact of extracorporeal membrane oxygenation (ECMO) on lung-kidney interactions is evaluated, highlighting its role in severe respiratory failure and its renal implications. Emerging therapies, such as mesenchymal stem cells and extracellular vesicles, are discussed as promising avenues to mitigate organ damage and enhance outcomes in critically ill patients. Overall, this review offers a nuanced exploration of lung-kidney dynamics, bridging historical insights with contemporary perspectives. It underscores the clinical significance of these interactions in critically ill patients and advocates for integrated management approaches to optimize patient outcomes.

16.
J Extracell Vesicles ; 13(8): e12496, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39113589

RESUMO

Parasitic diseases have a significant impact on human and animal health, representing a major hazard to the public and causing economic and health damage worldwide. Extracellular vesicles (EVs) have long been recognized as diagnostic and therapeutic tools but are now also known to be implicated in the natural history of parasitic diseases and host immune response modulation. Studies have shown that EVs play a role in parasitic disease development by interacting with parasites and communicating with other types of cells. This review highlights the most recent research on EVs and their role in several aspects of parasite-host interactions in five key parasitic diseases: Chagas disease, malaria, toxoplasmosis, leishmaniasis and helminthiases. We also discuss the potential use of EVs as diagnostic tools or treatment options for these infectious diseases.


Assuntos
Vesículas Extracelulares , Interações Hospedeiro-Parasita , Doenças Parasitárias , Humanos , Vesículas Extracelulares/metabolismo , Animais , Doenças Parasitárias/terapia , Doenças Parasitárias/diagnóstico , Doenças Parasitárias/imunologia , Doença de Chagas/terapia , Doença de Chagas/diagnóstico , Doença de Chagas/imunologia
17.
Biochim Biophys Acta Gen Subj ; 1868(10): 130684, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39084330

RESUMO

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.


Assuntos
Albuminas , Angiotensina II , Endocitose , Células Epiteliais , Glucose , Túbulos Renais Proximais , Receptor Tipo 1 de Angiotensina , Endocitose/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Angiotensina II/farmacologia , Glucose/metabolismo , Glucose/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Albuminas/metabolismo , Suínos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Losartan/farmacologia
18.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167155, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38579939

RESUMO

Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression.


Assuntos
Endocitose , Túbulos Renais Proximais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Endocitose/efeitos dos fármacos , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/virologia , Animais , Glicoproteína da Espícula de Coronavírus/metabolismo , SARS-CoV-2/metabolismo , Células HEK293 , Suínos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosforilação , COVID-19/metabolismo , COVID-19/virologia , COVID-19/patologia , Albuminas/metabolismo , Células LLC-PK1 , Células Epiteliais/metabolismo , Células Epiteliais/virologia
19.
Crit Care Med ; 41(4): 1056-68, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23385098

RESUMO

OBJECTIVE: It is well known that sepsis causes damage in different organs, including kidneys. However, few studies have been conducted on the magnitude of the long-term effects of sepsis on the surviving population, in particular, in relation to kidney disease. In this study, we examined the impact of long-term effects of sepsis on a second kidney insult. DESIGN: Prospective experimental study. SETTING: University research laboratory. INTERVENTIONS: Wild-type mice were subjected to the cecal ligation and puncture sepsis model. Control animals underwent identical laparotomy but without ligation and cecum puncture. On days 0, 7, and 14 after surgery, the ratio between urinary protein and creatinine was measured. Fifteen days after surgery, surviving mice were subjected to a second kidney insult through intraperitoneal injections of bovine serum albumin for 7 days. On day 22 after surgery, urinary protein and creatinine, γ-glutamyl transpeptidase, lactate dehydrogenase, histologic parameters, macrophage infiltration, apoptotic cell, renal and plasmatic cytokines were determined. MEASUREMENTS AND MAIN RESULTS: On days 7 and 14 after surgery, the urinary protein and creatinine observed in the septic animal group were higher than those observed in the control group. On day 22 after surgery, sepsis-surviving animals that were subjected to a second kidney insult showed more severe tubular injury compared with controls. This process seems to involve an immunosuppressive state because the concentrations of some renal cytokines, such as tumor necrosis factor-α, interleukin 6, interferon-γ and chemokine ligand 2, were decreased and leukocyte numbers were increased. CONCLUSIONS: These results suggest that sepsis induces long-term effects in kidney structure aggravating tubule damage in a second kidney insult.


Assuntos
Injúria Renal Aguda/patologia , Injúria Renal Aguda/urina , Choque Séptico/patologia , Choque Séptico/urina , Injúria Renal Aguda/diagnóstico , Animais , Biomarcadores/urina , Ceco , Modelos Animais de Doenças , Camundongos , Estudos Prospectivos , Punções , Distribuição Aleatória , Valores de Referência
20.
Eur J Pharmacol ; 942: 175521, 2023 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-36681317

RESUMO

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ratos , Animais , Nefropatias Diabéticas/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Albuminúria , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Transportador 2 de Glucose-Sódio/metabolismo , Proteínas/metabolismo , Albuminas/metabolismo , Glucose/efeitos adversos
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