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1.
Biomed Pharmacother ; 138: 111465, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311522

RESUMO

Acidic mammalian chitinase (CHIA) belongs to the 18-glycosidase family and is expressed in epithelial cells and certain immune cells (such as neutrophils and macrophages) in various organs. Under physiological conditions, as a hydrolase, CHIA can degrade chitin-containing pathogens, participate in Type 2 helper T (Th2)-mediated inflammation, and enhance innate and adaptive immunity to pathogen invasion. Under pathological conditions, such as rhinitis, ocular conjunctivitis, asthma, chronic atrophic gastritis, type 2 diabetes, and pulmonary interstitial fibrosis, CHIA expression is significantly changed. In addition, studies have shown that CHIA has an anti-apoptotic effect, promotes epithelial cell proliferation and maintains organ integrity, and these effects are not related to chitinase degradation. CHIA can also be used as a biomolecular marker in diseases such as chronic atrophic gastritis, dry eye, and acute kidney damage caused by sepsis. Analysis of the authoritative TCGA database shows that CHIA expression in gastric adenocarcinoma, liver cancer, renal clear cell carcinoma and other tumors is significantly downregulated compared with that in normal tissues, but the specific mechanism is unclear. This review is based on all surveys conducted to date and summarizes the expression patterns and functional diversity of CHIA in various organs. Understanding the physiological and pathophysiological relevance of CHIA in multiple organs opens new possibilities for disease treatment.


Assuntos
Encéfalo/enzimologia , Quitinases/metabolismo , Sistema Digestório/enzimologia , Olho/enzimologia , Rim/enzimologia , Sistema Respiratório/enzimologia , Animais , Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Sistema Digestório/fisiopatologia , Olho/fisiopatologia , Humanos , Rim/fisiopatologia , Sistema Respiratório/fisiopatologia , Transdução de Sinais
2.
Nutrients ; 13(6)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200606

RESUMO

Algae are potential and natural source of long-chain polyunsaturated fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The diatom Pinnularia borealis accumulates high levels of EPA and may be considered as a source for commercial production of dietary supplements. In this study we asked the question whether diet supplementation with P. borealis may augment antioxidant defense and ameliorate risk factors for cardiovascular diseases. We fed mice (Mus musculus) with lyophilized diatom solutions of different concentrations (1%, 3%, and 5%) for 7 days. Then we measured glutathione content and the activity of glutathione redox system enzymes, total cholesterol and triacylglycerol concentrations, and malondialdehyde concentration in the liver and kidney. We found that cholesterol and triacylglycerol concentrations in the liver and kidneys were the lowest in mice who were fed with the highest concentration of Pinnularia borealis, suggesting protective properties of algae. Additionally, the lowest concentration of Pinnularia borealis was sufficient to improve antioxidant capacity. Our results suggest that P. borealis may be used as a source for dietary supplements rich in EPA, but the amount supplied to the organism should be limited.


Assuntos
Diatomáceas/química , Suplementos Nutricionais , Glutationa/metabolismo , Rim/enzimologia , Fígado/enzimologia , Animais , Liofilização , Masculino , Camundongos
3.
Life Sci ; 282: 119843, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34298037

RESUMO

AIMS: Ischemia/reperfusion (I/R) occurs in renal artery stenosis, partial nephrectomy and most commonly during kidney transplantation. It brings serious consequences such as DGF (Delayed Graft Function) or organ dysfunction leading to renal failure and ultimate death. There is no effective therapy to handle the consequences of Renal Ischemia/Reperfusion (I/R) injury. Cyclic nucleotides, cAMP and cGMP are the important second messengers that stimulate intracellular signal transduction for cell survival in response to growth factors and peptide hormones in normal tissues and in kidneys plays significant role that involves vascular tone regulation, inflammation and proliferation of parenchymal cells. Renal ischemia and subsequent reperfusion injury stimulate signal transduction pathways involved in oxidative stress, inflammation, alteration in renal blood flow leading to necrosis and apoptosis of renal cell. MATERIALS AND METHODS: An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out. To understand the functioning of Phosphodiesterases (PDEs) and its pharmacological modulation in Renal Ischemia-Reperfusion Injury. KEY FINDINGS: Current therapeutic options may not be enough to treat renal I/R injury in group of patients and therefore, the current review has discussed the general characteristics and physiology of PDEs and preclinical-studies defining the relationship between PDEs expression in renal injury due to I/R and its outcome on renal function. SIGNIFICANCE: The role of PDE inhibitors in renal I/R injury and the clinical status of drugs for various renal diseases have been summarized in this review.


Assuntos
Nefropatias , Rim/enzimologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Traumatismo por Reperfusão , Transdução de Sinais/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/enzimologia , Nefropatias/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologia
5.
Cells ; 10(3)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803290

RESUMO

Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK (TAM) receptors signaling has shown immunomodulatory activity in sepsis, here we sought to determine whether Gas6 protein injection could mitigate MOF in a cecal slurry mouse model of sepsis. Mice, divided into different groups according to treatment-i.e., placebo (B), ampicillin (BA), Gas6 alone (BG), and ampicillin plus Gas6 (BAG)-were assessed for vitality, histopathology and cytokine expression profile as well as inducible nitric oxide synthase (iNOS), ALT and LDH levels. BAG-treated mice displayed milder kidney and lung damage and reduced levels of cytokine expression and iNOS in the lungs compared to BA-treated mice. Notably, BAG-treated mice showed lower LDH levels compared to controls. Lastly, BAG-treated cells of dendritic, endothelial or monocytic origin displayed reduced ROS formation and increased cell viability, with a marked upregulation of mitochondrial activity. Altogether, our findings indicate that combined treatment with Gas6 and antibiotics ameliorates sepsis-induced organ damage and reduces systemic LDH levels in mice, suggesting that Gas6 intravenous injection may be a viable therapeutic option in sepsis.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Especificidade de Órgãos , Espécies Reativas de Oxigênio/metabolismo , Sepse/tratamento farmacológico , Sepse/patologia , Animais , Sobrevivência Celular , Ativação Enzimática , Hematopoese , Homeostase , Rim/enzimologia , Rim/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Células RAW 264.7 , Receptores Proteína Tirosina Quinases/metabolismo , c-Mer Tirosina Quinase/metabolismo
6.
Am J Physiol Renal Physiol ; 320(5): F972-F983, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33818125

RESUMO

Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies have demonstrated that peptides in the ribonuclease A superfamily have antimicrobial activity against uropathogens and protect the urinary tract from uropathogenic Escherichia coli (UPEC). Little is known about the antibacterial function or expression of ribonuclease 4 (RNase 4) in the human urinary tract. Here, we show that full-length recombinant RNase 4 peptide and synthetic amino-terminal RNase 4 peptide fragment have antibacterial activity against UPEC and multidrug-resistant (MDR)-UPEC. RNASE4 transcript expression was detected in human kidney and bladder tissue using quantitative real-time PCR. Immunostaining or in situ hybridization localized RNase 4 expression to proximal tubules, principal and intercalated cells in the kidney's collecting duct, and the bladder urothelium. Urinary RNase 4 concentrations were quantified in healthy controls and females with a history of urinary tract infection. Compared with controls, urinary RNase 4 concentrations were significantly lower in females with a history of urinary tract infection. When RNase 4 was neutralized in human urine or silenced in vitro using siRNA, urinary UPEC replication or attachment to and invasion of urothelial and kidney medullary cells increased. These data show that RNase 4 has antibacterial activity against UPEC, is expressed in the human urinary tract, and can contribute to host defense against urinary tract infections.NEW & NOTEWORTHY Ribonuclease 4 (RNase 4) is a newly identified host defense peptide in the human kidney and bladder. RNase 4 kills uropathogenic Escherichia coli (UPEC) and multidrug-resistant UPEC. RNase 4 prevents invasive UPEC infection and suppressed RNase 4 expression may be a risk factor for more severe or recurrent urinary tract infection.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Rim/enzimologia , Ribonucleases/metabolismo , Bexiga Urinária/enzimologia , Adolescente , Peptídeos Catiônicos Antimicrobianos , Criança , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Feminino , Inativação Gênica , História Antiga , História Medieval , Humanos , Rim/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ribonucleases/genética , Ribonucleases/urina , Bexiga Urinária/metabolismo , Escherichia coli Uropatogênica , Urotélio/citologia
7.
Mar Drugs ; 19(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810216

RESUMO

Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Modelos Animais de Doenças , Rim/enzimologia , Rim/patologia , Nefropatias/enzimologia , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Nefrectomia , Biogênese de Organelas , Processamento de Proteína Pós-Traducional , Ratos Sprague-Dawley , Transdução de Sinais
8.
Am J Physiol Renal Physiol ; 320(5): F706-F718, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33719570

RESUMO

Cellular metabolic rates in the kidney are critical for maintaining normal renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting in the generation of pyruvate and NADH. In the absence of oxidative phosphorylation, the continuation of glycolysis is dependent on the regeneration of NAD+ from NADH accompanied by the fermentation of pyruvate to lactate. This reaction is catalyzed by lactate dehydrogenase (LDH) isoform A (LDHA), whereas LDH isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker as it is released from damaged cells into the urine and serum; however, the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry results and single-cell RNA-sequencing data on healthy mouse kidneys, we identified that LDHA is primarily expressed in proximal segments, whereas LDHB is expressed in the distal parts of the nephron. In vitro experiments in mouse and human renal proximal tubule cells showed an increase in LDHA following hypoxia with no change in LDHB. Using immunofluorescence, we observed that the overall expression of both LDHA and LDHB proteins decreased following renal ischemia-reperfusion injury as well as in the adenine-diet-induced model of chronic kidney disease. Single-nucleus RNA-sequencing analyses of kidneys following ischemia-reperfusion injury revealed a significant decline in the number of cells expressing detectable levels of Ldha and Ldhb; however, cells that were positive showed increased average expression postinjury, which subsided during the recovery phase. These data provide information on the cell-specific expression of LDHA and LDHB in the normal kidney as well as following acute and chronic kidney disease.NEW & NOTEWORTHY Cellular release of lactate dehydrogenase (LDH) is being used as an injury marker; however, the exact localization of LDH within the nephron remains unclear. We show that LDH isoform A is expressed proximally, whereas isoform B is expressed distally. Both subunit expressions were significantly altered in models of acute kidney injury and chronic kidney disease. Our study provides new insights into basal and postinjury renal lactate metabolism.


Assuntos
Injúria Renal Aguda/enzimologia , Rim/enzimologia , L-Lactato Desidrogenase/metabolismo , Insuficiência Renal Crônica/enzimologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Animais , Biomarcadores/metabolismo , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Humanos , Isoenzimas , Rim/patologia , L-Lactato Desidrogenase/genética , Masculino , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Fatores de Tempo
9.
Am J Physiol Renal Physiol ; 320(5): F734-F747, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33682442

RESUMO

The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K+ and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Rim/enzimologia , Proteínas dos Microfilamentos/metabolismo , Potássio na Dieta/metabolismo , Pseudo-Hipoaldosteronismo/enzimologia , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Culina/metabolismo , Estabilidade Enzimática , Feminino , Rim/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Mutação , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/deficiência , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Xenopus laevis
10.
Toxins (Basel) ; 13(2)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33671978

RESUMO

The purpose of this study was to investigate the potential of a byproduct mixture derived from grapeseed and sea buckthorn oil industry to mitigate the harmful damage produced by ochratoxin A and aflatoxin B1 at hepatic and renal level in piglets after weaning. Forty cross-bred TOPIGS-40 hybrid piglets after weaning were assigned to three experimental groups (E1, E2, E3) and one control group (C), and fed with experimental diets for 30 days. The basal diet was served as a control and contained normal compound feed for starter piglets without mycotoxins. The experimental groups were fed as follows: E1-basal diet plus a mixture (1:1) of two byproducts (grapeseed and sea buckthorn meal); E2-the basal diet experimentally contaminated with mycotoxins (479 ppb OTA and 62ppb AFB1); and E3-basal diet containing 5% of the mixture (1:1) of grapeseed and sea buckthorn meal and contaminated with the mix of OTA and AFB1. After 4 weeks, the animals were slaughtered, and tissue samples were taken from liver and kidney in order to perform gene expression and histological analysis. The gene expression analysis showed that when weaned piglets were fed with contaminated diet, the expression of most analyzed genes was downregulated. Among the CYP450 family, CYP1A2 was the gene with the highest downregulation. According to these results, in liver, we found that mycotoxins induced histomorphological alterations in liver and kidney and had an effect on the expression level of CYP1A2, CYP2A19, CYP2E1, and CYP3A29, but we did not detect important changes in the expression level of CY4A24, MRP2 and GSTA1 genes.


Assuntos
Aflatoxina B1/toxicidade , Antioxidantes/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Suplementos Nutricionais , Resíduos Industriais , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ocratoxinas/toxicidade , Ração Animal/microbiologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Exposição Dietética , Manipulação de Alimentos , Microbiologia de Alimentos , Regulação Enzimológica da Expressão Gênica , Hippophae , Rim/enzimologia , Rim/patologia , Fígado/enzimologia , Fígado/patologia , Óleos Vegetais , Sus scrofa , Vitis , Desmame
11.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670516

RESUMO

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.


Assuntos
Injúria Renal Aguda/metabolismo , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Nefropatias/metabolismo , Estresse Oxidativo , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/patologia , Animais , Humanos , Rim/citologia , Rim/enzimologia , Rim/metabolismo , Nefropatias/enzimologia , Nefropatias/patologia , Túbulos Renais/citologia , Túbulos Renais/enzimologia , Túbulos Renais/metabolismo , Substâncias Protetoras/metabolismo
12.
Am J Physiol Renal Physiol ; 320(5): F789-F798, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33615888

RESUMO

Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAß. Although the renal phenotype of CnAα-/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAα are poorly understood. Since NADPH oxidase-2 (Nox2)-derived oxidative damage has been implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress. To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα-/-, CnAß-/-, and wild-type (WT) littermate mice. To identify the downstream mediator of CnAα, nuclear factor of activated T cells (NFAT) and NF-κB regulation was examined. To test if Nox2 is transcriptionally regulated via a NF-κB pathway, CnAα-/- and WT renal fibroblasts were treated with the NF-κB inhibitor caffeic acid phenethyl ester. Our findings showed that cyclosporine A treatment induced Nox2 upregulation and oxidative stress. Furthermore, Nox2 upregulation and elevated ROS generation occurred only in CnAα-/- mice. In these mice, NF-κB but not NFAT activity was increased. In CnAα-/- renal fibroblasts, NF-κB inhibition prevented Nox2 upregulation and reactive oxygen species (ROS) generation. In conclusion, these findings indicate that 1) CnAα loss stimulates Nox2 upregulation, 2) NF-κB is a novel CnAα-regulated transcription factor, and 3) NF-κB mediates CnAα-induced Nox2 and ROS regulation. Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Furthermore, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity.NEW & NOTEWORTHY A long-term consequence of calcineurin inhibitors (CNIs) is oxidative damage and nephrotoxicity. This study indicates that NF-κB is a novel calcineurin-regulated transcription factor that is activated with calcineurin inhibition, thereby driving oxidative damage in CNI nephropathy. These findings provide additional evidence of divergent calcineurin signaling pathways and suggest that selective CNIs could improve the long-term outcomes of patients by mitigating renal side effects.


Assuntos
Inibidores de Calcineurina/toxicidade , Calcineurina/metabolismo , Ciclosporina/toxicidade , Imunossupressores/toxicidade , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Animais , Calcineurina/deficiência , Calcineurina/genética , Linhagem Celular , Fibrose , Rim/enzimologia , Rim/patologia , Nefropatias/enzimologia , Nefropatias/genética , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
13.
Biomolecules ; 11(2)2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578980

RESUMO

Chronic kidney disease of unknown etiology (CKDu) has been recognized as a global non-communicable health issue. There are many proposed risk factors for CKDu and the exact reason is yet to be discovered. Understanding the inhibition or manipulation of vital renal enzymes by pesticides can play a key role in understanding the link between CKDu and pesticides. Even though it is very important to take metabolites into account when investigating the relationship between CKDu and pesticides, there is a lack of insight regarding the effects of pesticide metabolites towards CKDu. In this study, a computational approach was used to study the effects of pesticide metabolites on CKDu. Further, interactions of selected pesticides and their metabolites with renal enzymes were studied using molecular docking and molecular dynamics simulation studies. It was evident that some pesticides and metabolites have affinity to bind at the active site or at regulatory sites of considered renal enzymes. Another important discovery was the potential of some metabolites to have higher binding interactions with considered renal enzymes compared to the parent pesticides. These findings raise the question of whether pesticide metabolites may be a main risk factor towards CKDu.


Assuntos
Biologia Computacional/métodos , Rim/enzimologia , Praguicidas/efeitos adversos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , Sítios de Ligação , Domínio Catalítico , Progressão da Doença , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Análise de Componente Principal , Ligação Proteica , Fatores de Risco , Solventes
14.
Artigo em Inglês | MEDLINE | ID: mdl-33610817

RESUMO

This study aimed, for the first time, to assess the purification of aldose reductase (AR) in Jaculus orientalis (Dipodidae family) kidney and to evaluate the in vitro aldose reductase inhibitory (ARI) effects of Euphorbia regis-jubae (Euphorbiaceae family) aqueous and hydroethanolic extracts. Initial screening assay of the enzymatic AR activity in different jerboa states (euthermic, prehibernating and hibernating) and tissues (brain, brown adipose tissue, liver and kidneys) was assessed. Then, AR has been purified to homogeneity from the kidneys of prehibernating jerboas by a series of chromatographic technics. Furthermore, the in vitro and in silico ARI effects of E. regis-jubae (Webb & Berth) extracts, characterized by hight performance liquid chromatography (HPLC) on the purified enzyme were evaluated. Our results showed that the highest enzyme activity was detected in the kidneys, followed by white adipose tissue and the lungs of pre-hibernating jerboa. The enzyme was purified to homogeneity from jerboa kidneys during prehibernating state with a purification factor of 53.4-fold and a yield of about 6%. AR is monomeric, active in D(+)-glyceraldehyde substrate and in disodium phosphate buffer. The pH and temperature for AR were determined to be 6.5-7.5 and 35 °C, respectively. Results of the in vitro ARI activity was strongest with both the hydroethanolic extract (IC50 = 96.45 µg/mL) and aqueous extract (IC50 = 140 µg/mL). Molecular docking study indicated that catechin might be the main component in both aqueous and hydroethanolic extracts to inhibited AR. This study provides new evidence on the ARI effect of E. regis-jubae (Webb & Berth), which may be related to its phenolic constituents.


Assuntos
Aldeído Redutase , Inibidores Enzimáticos/farmacologia , Euphorbia/química , Extratos Vegetais/farmacologia , Roedores , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/isolamento & purificação , Animais , Hibernação , Rim/enzimologia
15.
Toxicol Appl Pharmacol ; 416: 115465, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631230

RESUMO

Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN.


Assuntos
Anti-Inflamatórios/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Nefrite/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Quinase 9 Dependente de Ciclina/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Fibrose , Mediadores da Inflamação/metabolismo , Rim/enzimologia , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nefrite/enzimologia , Nefrite/etiologia , Nefrite/patologia , Fator de Transcrição AP-1/metabolismo
16.
Korean J Intern Med ; 36(2): 247-262, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33617712

RESUMO

In the decades since the discovery of angiotensin-converting enzyme 2 (ACE2), its protective role in terms of antagonizing activation of the classical renin-angiotensin system (RAS) axis has been recognized in clinical and experimental studies on kidney and cardiovascular diseases. The effects of ACE inhibitor/angiotensin type 1 receptor blockers (ACEi/ARBs) on ACE2-angiotensin-(1-7) (Ang- (1-7))-Mas receptor (MasR) axis activation has encouraged the use of such blockers in patients with kidney and cardiovascular diseases, until the emergence of coronavirus disease 2019 (COVID-19). The previously unchallenged functions of the ACE2-Ang-(1-7)-MasR axis and ACEi/ARBs are being re-evaluated in the era of COVID-19; the hypothesis is that ACEi/ARBs may increase the risk of severe acute respiratory syndrome coronavirus 2 infection by upregulating the human ACE2 receptor expression level. In this review, we examine ACE2 molecular structure, function (as an enzyme of the RAS), and distribution. We explore the roles played by ACE2 in kidney, cardiovascular, and pulmonary diseases, highlighting studies that defined the benefits imparted when ACEi/ARBs activated the local ACE2- Ang-(1-7)-MasR axis. Finally, the question of whether ACEi/ARBs therapies should be stopped in COVID-19-infected patients will be reviewed by reference to the available evidence.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Nefropatias/enzimologia , Rim/enzimologia , Receptores Virais/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/patogenicidade , Internalização do Vírus , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , COVID-19/enzimologia , Interações Hospedeiro-Patógeno , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2/metabolismo
17.
Sci Rep ; 11(1): 2089, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483569

RESUMO

Microplastic and nanoplastic particles are prevalent in the environment and are beginning to enter the living system through multiple channels. Currently, little is known about the impact of plastic nanoparticles in living organisms. In order to investigate the health impact of micro- and nanoparticles of common polymers in a systematic way, luminescent plastic nanoparticles from two common polymers, polyvinyl chloride (PVC) and poly (methyl methacrylate) (PMMA) with relatively narrow size distribution are prepared using a nanoprecipitation method. As a model system, BHK-21 cells were exposed to polymer nanoparticles to understand the mode of uptake, internalization and biochemical changes inside the cells. The cellular effects of the nanoparticles were evaluated by monitoring the changes in cell viability, cell morphology, concentrations of reactive oxygen species (ROS), adenine triphosphate (ATP) and lactate dehydrogenase at different concentrations of the nanoparticles and time of exposure. PVC and PMMA nanoparticles induced a reduction in the cell viability along with a reduction of ATP and increase of ROS concentrations in a dose- and time-dependent manner. The plastic nanoparticles are internalized into the cell via endocytosis, as confirmed by Dynasore inhibition assay and colocalization with latex beads. Our findings suggest that plastic nanoparticle internalization could perturb cellular physiology and affect cell survival under laboratory conditions.


Assuntos
Nanopartículas/química , Polimetil Metacrilato/química , Cloreto de Polivinila/química , Trifosfato de Adenosina/metabolismo , Animais , Ciclo Celular , Linhagem Celular , Cricetinae , Endocitose , Rim/citologia , Rim/enzimologia , Rim/metabolismo , L-Lactato Desidrogenase/metabolismo , Microscopia Eletrônica de Varredura , Espécies Reativas de Oxigênio/metabolismo
18.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401733

RESUMO

Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay is a long-established assay used to detect cell death-associated DNA fragmentation (3'-OH DNA termini) by endonucleases. Because these enzymes are particularly active in the kidney, TUNEL is widely used to identify and quantify DNA fragmentation and cell death in cultured kidney cells and animal and human kidneys resulting from toxic or hypoxic injury. The early characterization of TUNEL as an apoptotic assay has led to numerous misinterpretations of the mechanisms of kidney cell injury. Nevertheless, TUNEL is becoming increasingly popular for kidney injury assessment because it can be used universally in cultured and tissue cells and for all mechanisms of cell death. Furthermore, it is sensitive, accurate, quantitative, easily linked to particular cells or tissue compartments, and can be combined with immunohistochemistry to allow reliable identification of cell types or likely mechanisms of cell death. Traditionally, TUNEL analysis has been limited to the presence or absence of a TUNEL signal. However, additional information on the mechanism of cell death can be obtained from the analysis of TUNEL patterns.


Assuntos
Apoptose/genética , Fragmentação do DNA , Marcação In Situ das Extremidades Cortadas/métodos , Nefropatias/diagnóstico , Animais , Células Cultivadas , Desoxirribonucleases/metabolismo , Endonucleases/metabolismo , Humanos , Rim/citologia , Rim/enzimologia , Rim/lesões , Rim/patologia , Nefropatias/enzimologia , Nefropatias/fisiopatologia
19.
Biomed Pharmacother ; 135: 111180, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33433354

RESUMO

BACKGROUND AND PURPOSE: Indolamine 2,3-dioxygenase (IDO), an enzyme that catalyses the metabolism of tryptophan, may play a detrimental role in ischemia-reperfusion injury (IRI). IDO can be inhibited by 1-methyl-tryptophan, which exists in a D (D-MT) or L (L-MT) isomer. These forms show different pharmacological effects besides IDO inhibition. Therefore, we sought to investigate whether these isomers can play a protective role in renal IRI, either IDO-dependent or independent. EXPERIMENTAL APPROACH: We studied the effect of both isomers in a rat renal IRI model with a focus on IDO-dependent and independent effects. KEY RESULTS: Both MT isomers reduced creatinine and BUN levels, with D-MT having a faster onset of action but shorter duration and L-MT a slower onset but longer duration (24 h and 48 h vs 48 h and 96 h reperfusion time). Interestingly, this effect was not exclusively dependent on IDO inhibition, but rather from decreased TLR4 signalling, mimicking changes in renal function. Additionally, L-MT increased the overall survival of rats. Moreover, both MT isomers interfered with TGF-ß signalling and epithelial-mesenchymal transition. In order to study the effect of isomers in all mechanisms involved in IRI, a series of in vitro experiments was performed. The isomers affected signalling pathways in NK cells and tubular epithelial cells, as well as in dendritic cells and T cells. CONCLUSION AND IMPLICATIONS: This study shows that both MT isomers have a renoprotective effect after ischemia-reperfusion injury, mostly independent of IDO inhibition, involving mutually different mechanisms. We bring novel findings in the pharmacological properties and mechanism of action of MT isomers, which could become a novel therapeutic target of renal IRI.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Triptofano/análogos & derivados , Animais , Técnicas de Cocultura , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/enzimologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Rim/enzimologia , Rim/patologia , Nefropatias/enzimologia , Nefropatias/patologia , Lectinas Tipo C/metabolismo , Camundongos , Células NIH 3T3 , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triptofano/farmacologia
20.
Int Immunopharmacol ; 90: 107123, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33168411

RESUMO

Sepsis is a life-threatening condition which affects multiple organs including the kidney. Sepsis-induced acute kidney injury (AKI) is a major health burden throughout the globe. Pathogenesis of sepsis-induced AKI is complex; however, it involves both innate and adaptive immune cells such as B cells, T cells, dendritic cells (DCs), macrophages, and neutrophils. Bruton's tyrosine kinase (BTK) is reportedly involved in inflammatory and oxidative signaling in different immune cells, however its contribution with respect to sepsis-induced AKI has not been delineated. This study attempted to investigate the role of BTK and its inhibition on oxidizing enzymes NADPH oxidase (NOX-2) and inducible nitric oxide synthase (iNOS) in DCs, neutrophils, and B cells during AKI. Our data reveal that BTK is activated in DCs, neutrophils, and B cells which causes an increase in AKI associated biochemical markers such as serum creatinine/blood urea nitrogen, renal myeloperoxidase activity, and histopathological disturbances in renal tubular structures. Activation of BTK causes upregulation of NOX-2/iNOS/nitrotyrosine in these immune cells and kidney. Treatment with BTK inhibitor, Ibrutinib causes attenuation in AKI associated dysfunction in biochemical parameters (serum creatinine/blood urea nitrogen, renal myeloperoxidase activity) and oxidative stress in immune cells and kidney (iNOS/NOX2/lipid peroxides/nitrotyrosine/protein carbonyls). In summary, the current investigation reveals a compelling role of BTK signaling in sepsis-induced AKI which is evident from amelioration of AKI associated renal dysfunction after its inhibition.


Assuntos
Injúria Renal Aguda/prevenção & controle , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Rim/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Sepse/tratamento farmacológico , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Linfócitos B/enzimologia , Linfócitos B/imunologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Rim/enzimologia , Rim/imunologia , Rim/patologia , Masculino , Camundongos Endogâmicos BALB C , NADPH Oxidase 2/metabolismo , Neutrófilos/enzimologia , Neutrófilos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Sepse/enzimologia , Sepse/imunologia , Transdução de Sinais
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