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1.
Anticancer Res ; 40(11): 6525-6530, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109593

RESUMO

BACKGROUND/AIM: End-stage kidney disease is characterized by chronic inflammation and frequent development of cancer. The level of circulating vitamin D is generally low in patients with end-stage renal disease (ESRD). Experimental studies have implicated the role of dysfunctional vitamin D metabolism in tumorigenesis. PATIENTS AND METHODS: We analyzed the expression of vitamin D receptor (VDR), cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), the key genes involved in vitamin D signaling, in kidneys from patients with ESRD, tissue microarrays containing ESRD-associated renal cell tumors, as well as in their precursor lesions by immunohistochemistry. RESULTS: Kidneys from patients with ESRD showed strong structural rearrangement with only few tubules and epithelial cell groups embedded in fibrotic-inflammatory stroma. Only an estimated 1-3% of the epithelial cells showed positive staining with antibodies to VDR, CYP27B1 and CYP24A1, which contrasted with the 100%, 40-50% and 40-50% of positively stained cells, respectively, found in normal kidneys. Down-regulation of the vitamin D signaling proteins was found in patients with renal cancer, with the exception of tumors and their precursors occurring exclusively in ESRD. CONCLUSION: The significantly reduced activity of CYP27B1 in kidney from patients with ESRD explains the low level of circulating vitamin D. We suggest that the lack of anti-tumorigenic effect of vitamin D is a crucial factor in the frequent development of unique types of renal cell cancer in in patients with ESRD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Carcinoma de Células Renais/genética , Falência Renal Crônica/genética , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Redes e Vias Metabólicas/genética , Vitamina D/sangue
3.
Toxicol Lett ; 334: 36-43, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941993

RESUMO

Cisplatin is a widely used chemotherapeutic agent. However, it is causing nephrotoxic side effects including a reduced glomerular filtration rate and acute kidney injury. Although kidneys can recover to an extent from the treatment, long-term damage is possible. While a lot of research is focusing on short-term effects, little is known about adverse metabolic effects in the process of recovery. In this study, male Han Wistar rats were dosed with a single intraperitoneal injection of 3 mg/kg cisplatin. Urine and kidney samples were harvested 3, 8 and 26 days after administration. Tubular injury was demonstrated through urinary biomarkers. Complementing this, mass spectrometry imaging gives insight on molecular alterations on a spatial level, thus making it well suited to analyze short- and long-term disturbances. Various metabolic pathways seem to be affected, as changes in a wide range of metabolites were observed between treated and control animals. Besides previously reported early changes in kidney metabolism, unprecedented long-term effects were detected including deviation in nucleotides, antioxidants, and phospholipids.


Assuntos
Antineoplásicos/toxicidade , Antioxidantes/metabolismo , Cisplatino/toxicidade , Metabolismo Energético/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Injeções Intraperitoneais , Rim/metabolismo , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Ratos Wistar , Fatores de Tempo
4.
BMC Nephrol ; 21(1): 326, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753052

RESUMO

BACKGROUND: Coronavirus disease-2019 (COVID-19) is an ongoing pandemic which has affected over 12 million people across the globe. Manifestations in different organs systems are being reported regularly. Renal biopsy findings in hospitalized COVID-19 patients presenting solely with acute kidney injury (AKI) have recently been described in published literature in few case reports. The findings include diffuse acute tubular injury (ATI) along with the glomerular lesion of collapsing glomerulopathy (CG). However, nephrotic syndrome as the presenting complaint of COVID-19 has not been reported widely, neither has any other glomerular lesion other than CG. CASE PRESENTATION: We describe the kidney biopsy findings of two patients who had recent diagnoses of COVID-19 and presented with new-onset nephrotic syndrome. Renal biopsy in both patients showed ATI (as in previous reports) and distinct glomerular findings on light microscopy - that of minimal change disease (MCD) initially in one patient followed by CG in a subsequent biopsy and CG at the outset in the other patient. The electron microscopic findings in both patients were that of severe podocytopathy (diffuse and severe podocyte foot process effacement). CONCLUSION: Our cases highlight a novel clinical presentation of COVID-19 renal disease, not described before, that of new-onset nephrotic syndrome. While all published case reports describe CG as the glomerular pathology, we describe a non-CG pathology (MCD) in one of our cases, thereby adding to the repertoire of renal pathology described in association with COVID-19 patients. However, the exact mechanism by which podocyte injury or podocytopathy occurs in all such cases is still unknown. Optimal treatment options for these patients also remains unknown at this time.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Túbulos Renais/patologia , Síndrome Nefrótica/patologia , Pneumonia Viral/complicações , Podócitos/patologia , Idoso , Biópsia , Humanos , Rim/patologia , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/etiologia , Nefrose Lipoide/patologia , Síndrome Nefrótica/etiologia , Pandemias
5.
Life Sci ; 259: 118269, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798559

RESUMO

BACKGROUND: Diabetic nephropathy (DN), a severe microvascular complication of diabetes, has complex pathogenesis. Circular RNAs (circRNAs) exert broad biological functions on human diseases. This study intended to explore the role and mechanism of circ_WBSCR17 in DN. METHODS: DN mice models were constructed using streptozotocin injection, and DN cell models were assembled using high glucose (HG) treatment in human kidney 2 cells (HK-2). The expression of circ_WBSCR17, miR-185-5p and SRY-Box Transcription Factor 6 (SOX6) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of SOX6 and fibrosis markers were examined by western blot. The release of inflammatory cytokines, cell proliferation and apoptosis, were assessed by enzyme-linked immunosorbent assay (ELISA), cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The predicted interaction between miR-185-5p and circ_WBSCR17 or SOX6 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULT: Circ_WBSCR17 was highly expressed in DN mice models and HG-induced HK-2 cells. Circ_WBSCR17 knockdown or SOX6 knockdown promoted cell proliferation and blocked cell apoptosis, inflammatory responses and fibrosis, while circ_WBSCR17 overexpression or SOX6 overexpression conveyed the opposite effects. MiR-185-5p was a target of circ_WBSCR17 and directly bound to SOX6. MiR-185-5p could reverse the role of circ_WBSCR17 or SOX6. Moreover, the expression of SOX6 was modulated by circ_WBSCR17 through intermediating miR-185-5p. CONCLUSION: Circ_WBSCR17 triggered the dysfunction of HG-induced HK-2 cells, including inflammatory responses and fibrosis, which was accomplished via the miR-185-5p/SOX6 regulatory axis.


Assuntos
Nefropatias Diabéticas/metabolismo , Túbulos Renais/metabolismo , MicroRNAs/metabolismo , N-Acetilgalactosaminiltransferases/genética , RNA Circular/metabolismo , Fatores de Transcrição SOXD/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Fibrose/genética , Fibrose/metabolismo , Glucose/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Túbulos Renais/patologia , Túbulos Renais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , N-Acetilgalactosaminiltransferases/metabolismo , RNA Circular/genética , Fatores de Transcrição SOXD/genética
6.
Ecotoxicol Environ Saf ; 205: 111188, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32836151

RESUMO

Increasing evidence indicates autophagy and apoptosis are involved in the toxicity mechanism of heavy metals. Our previous studies showed that cadmium (Cd) could induce autophagy and apoptosis in duck kidneys in vivo, nevertheless, the interaction between them has yet to be elucidated. Herein, the cells were either treated with 3CdSO4·8H2O (0, 1.25, 2.5, 5.0 µM Cd) or/and 3-methyladenine (3-MA) (2.5 µM) for 12 h and the indictors related autophagy and apoptosis were detected to assess the correlation between autophagy and apoptosis induced by Cd in duck renal tubular epithelial cells. The results demonstrated that Cd exposure notably elevated intracellular and extracellular Cd contents, the number of autophagosomes and LC3 puncta, up-regulated LC3A, LC3B, Beclin-1, Atg5 mRNA levels, and Beclin-1 and LC3II/LC3I protein levels, down-regulated mTOR, p62 and Dynein mRNA levels and p62 protein level. Additionally, autophagy inhibitor 3-MA decreased Beclin-1, LC3II/LC3I protein levels and increased p62 protein level. Moreover, co-treatment with Cd and 3-MA could notably elevate Caspase-3, Cyt C, Bax, and Bak-1 mRNA levels, Caspase-3 and cleaved Caspase-3 protein levels, and cell apoptotic rate as well as cell damage, decreased mitochondrial membrane potential (MMP), Bcl-2 mRNA level and the ratio of Bcl-2 to Bax compared to treatment with Cd alone. Overall, these results indicate Cd exposure can induce autophagy in duck renal tubular epithelial cells, and inhibition of autophagy might aggravate Cd-induced apoptosis through mitochondria-mediated pathway.


Assuntos
Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cádmio/toxicidade , Patos , Células Epiteliais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Animais , Autofagossomos/metabolismo , Autofagossomos/patologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos
7.
J Am Soc Nephrol ; 31(9): 2158-2167, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32727719

RESUMO

BACKGROUND: AKI is common among hospitalized patients with coronavirus disease 2019 (COVID-19) and is an independent risk factor for mortality. Although there are numerous potential mechanisms underlying COVID-19-associated AKI, our current knowledge of kidney pathologic findings in COVID-19 is limited. METHODS: We examined the postmortem kidneys from 42 patients who died of COVID-19. We reviewed light microscopy findings in all autopsies and performed immunofluorescence, electron microscopy, and in situ hybridization studies for SARS-CoV-2 on a subset of samples. RESULTS: The cohort had a median age of 71.5 years (range, 38-97 years); 69% were men, 57% were Hispanic, and 73% had a history of hypertension. Among patients with available data, AKI developed in 31 of 33 patients (94%), including 6 with AKI stage 1, 9 with stage 2, and 16 with stage 3. The predominant finding correlating with AKI was acute tubular injury. However, the degree of acute tubular injury was often less severe than predicted for the degree of AKI, suggesting a role for hemodynamic factors, such as aggressive fluid management. Background changes of hypertensive arterionephrosclerosis and diabetic glomerulosclerosis were frequent but typically mild. We identified focal kidney fibrin thrombi in 6 of 42 (14%) autopsies. A single Black patient had collapsing FSGS. Immunofluorescence and electron microscopy were largely unrevealing, and in situ hybridization for SARS-CoV-2 showed no definitive positivity. CONCLUSIONS: Among a cohort of 42 patients dying with COVID-19, autopsy histologic evaluation revealed acute tubular injury, which was typically mild relative to the degree of creatinine elevation. These findings suggest potential for reversibility upon resolution of SARS-CoV-2 infection.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Rim/patologia , Pneumonia Viral/patologia , Lesão Renal Aguda/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Feminino , Humanos , Rim/ultraestrutura , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Pandemias
8.
Chem Biol Interact ; 328: 109189, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32622864

RESUMO

Di-n-butyl phthalate (DBP) is a pollutant that is widely present in the environment. We have previously demonstrated that maternal exposure to DBP resulted in renal fibrosis in offspring, but the underlying mechanism was not well elucidated. Therefore, the current study aims to understand the underlying molecular mechanisms in these sex-specific developmental alterations. Here, we used RNA-seq analysis to explore the underlying molecular mechanisms of DBP-associated renal fibrosis. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. Upregulated autophagy in renal tubules in offspring was confirmed in the DBP-treated group via accessing LC3Ⅱ/Ⅰ protein expression. Increased expression of the HhIP gene was found in the DBP-treated group via RNA-seq analysis. Immunohistochemistry (IHC) staining and Western blot analysis confirmed increased expression of HhIP protein and inhibited hedgehog signaling. Increased HhIP expression further leaded to impaired activation of hedgehog signaling, which is critical for normal embryonic development. Additional in vitro experiments on renal tubular cells suggest that inactivation of hedgehog signaling induced autophagy in renal tubular cells. Taken together, our findings show that maternal exposure to DBP induced autophagy through regulation of hedgehog signaling via overexpression of HhIP in foetal renal tubular cells, which may be essential for renal fibrosis development.


Assuntos
Autofagia , Dibutilftalato/toxicidade , Proteínas Hedgehog/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Linhagem Celular , Feminino , Túbulos Renais/efeitos dos fármacos , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
9.
PLoS One ; 15(6): e0235077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569271

RESUMO

Proteinuria and hyperphosphatemia are risk factors for cardiovascular disease in patients with chronic kidney disease (CKD). Although the interaction between proteinuria and the serum phosphate level is well established, the mechanistic link between the two, particularly the extent to which this interaction is mediated by phosphate-regulating factors, remains poorly understood. In this study, we examined the association between proteinuria and the serum phosphate level, as well as potential mediators, including circulating fibroblast growth factor (FGF23)/klotho, the 24-h urinary phosphate excretion rate to glomerular filtration rate ratio (EP/GFR), and the 24-h tubular phosphate reabsorption rate to GFR ratio (TRP/GFR). The analyses were performed with data from 1793 patients in whom 24-h urine protein and phosphate, serum phosphate, FGF23, and klotho levels were measured simultaneously, obtained from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable linear regression and mediation analyses were performed. Total, direct, and indirect effects were also estimated. Patients with high serum phosphate levels were found to be more likely to exhibit greater proteinuria, higher FGF23 levels, and lower klotho levels. The 24-h EP/GFR increased and the 24-h TRP/GFR decreased with increasing proteinuria and CKD progression. Simple mediation analyses showed that 15.4% and 67.9% of the relationship between proteinuria and the serum phosphate level were mediated by the FGF23/klotho ratio and 24-h EP/GFR, respectively. Together, these two factors accounted for 73.1% of the relationship between serum markers. These findings suggest that proteinuria increases the 24-h EP/GFR via the FGF23/klotho axis as a compensatory mechanism for the increased phosphate burden well before the reduction in renal function is first seen.


Assuntos
Fosfatos/sangue , Proteinúria/sangue , Insuficiência Renal Crônica/sangue , Estudos de Coortes , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Taxa de Filtração Glomerular , Glucuronidase/sangue , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Insuficiência Renal Crônica/fisiopatologia , República da Coreia , Resultado do Tratamento
10.
Life Sci ; 256: 117972, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544464

RESUMO

Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl2) increased the level of oxidative stress, up-regulated the production of pro-inflammatory factor, and induced apoptosis, ADK inhibition could alleviate the above damaging effects. Moreover, the anti-apoptotic effect exerted by ADK inhibition was independent of inosine. In summary, our results support the idea that ADK inhibition has protective effects on IR-induced AKI. Adenosine kinase inhibition might provide a new target for AKI prevention and treatment.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Adenosina Quinase/antagonistas & inibidores , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Traumatismo por Reperfusão/complicações , Adenosina Quinase/metabolismo , Adulto , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cobalto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Inflamação/patologia , Inosina/farmacologia , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Necrose , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/farmacologia
11.
PLoS One ; 15(6): e0234617, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555665

RESUMO

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.


Assuntos
Albuminúria/tratamento farmacológico , Alilamina/análogos & derivados , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Benzamidas/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Insuficiência Renal Crônica/tratamento farmacológico , Alilamina/farmacologia , Alilamina/uso terapêutico , Animais , Benzamidas/farmacologia , Diabetes Mellitus Experimental , Nefropatias Diabéticas/patologia , Inibidores Enzimáticos/farmacologia , Fibronectinas/metabolismo , Fibrose , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/patologia , Telmisartan/farmacologia , Telmisartan/uso terapêutico
12.
J Am Soc Nephrol ; 31(8): 1688-1695, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32561682

RESUMO

BACKGROUND: Kidney involvement is a feature of COVID-19 and it can be severe in Black patients. Previous research linked increased susceptibility to collapsing glomerulopathy, including in patients with HIV-associated nephropathy, to apo L1 (APOL1) variants that are more common in those of African descent. METHODS: To investigate genetic, histopathologic, and molecular features in six Black patients with COVID-19 presenting with AKI and de novo nephrotic-range proteinuria, we obtained biopsied kidney tissue, which was examined by in situ hybridization for viral detection and by NanoString for COVID-19 and acute tubular injury-associated genes. We also collected peripheral blood for APOL1 genotyping. RESULTS: This case series included six Black patients with COVID-19 (four men, two women), mean age 55 years. At biopsy day, mean serum creatinine was 6.5 mg/dl and mean urine protein-creatinine ratio was 11.5 g. Kidney biopsy specimens showed collapsing glomerulopathy, extensive foot process effacement, and focal/diffuse acute tubular injury. Three patients had endothelial reticular aggregates. We found no evidence of viral particles or SARS-CoV-2 RNA. NanoString showed elevated chemokine gene expression and changes in expression of genes associated with acute tubular injury compared with controls. All six patients had an APOL1 high-risk genotype. Five patients needed dialysis (two of whom died); one partially recovered without dialysis. CONCLUSIONS: Collapsing glomerulopathy in Black patients with COVID-19 was associated with high-risk APOL1 variants. We found no direct viral infection in the kidneys, suggesting a possible alternative mechanism: a "two-hit" combination of genetic predisposition and cytokine-mediated host response to SARS-CoV-2 infection. Given this entity's resemblance with HIV-associated nephropathy, we propose the term COVID-19-associated nephropathy to describe it.


Assuntos
Lesão Renal Aguda/genética , Apolipoproteína L1/genética , Infecções por Coronavirus/genética , Glomérulos Renais/virologia , Pneumonia Viral/genética , Lesão Renal Aguda/complicações , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Alelos , Biópsia , Infecções por Coronavirus/complicações , Creatinina/sangue , Feminino , Genótipo , Humanos , Rim/patologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Risco
13.
Int. j. morphol ; 38(3): 585-591, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098291

RESUMO

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.


El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.


Assuntos
Animais , Ratos , Quercetina/administração & dosagem , Resveratrol/administração & dosagem , Túbulos Renais/efeitos dos fármacos , Acetaminofen/toxicidade , Quercetina/farmacologia , Ureia/sangue , Ratos Sprague-Dawley , Creatinina/sangue , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Overdose de Drogas , Resveratrol/farmacologia , Túbulos Renais/patologia , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem
14.
J Am Soc Nephrol ; 31(8): 1683-1687, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32371536

RESUMO

BACKGROUND: A significant fraction of patients with coronavirus disease 2019 (COVID-19) display abnormalities in renal function. Retrospective studies of patients hospitalized with COVID-19 in Wuhan, China, report an incidence of 3%-7% progressing to ARF, a marker of poor prognosis. The cause of the renal failure in COVID-19 is unknown, but one hypothesized mechanism is direct renal infection by the causative virus, SARS-CoV-2. METHODS: We performed an autopsy on a single patient who died of COVID-19 after open repair of an aortic dissection, complicated by hypoxic respiratory failure and oliguric renal failure. We used light and electron microscopy to examine renal tissue for evidence of SARS-CoV-2 within renal cells. RESULTS: Light microscopy of proximal tubules showed geographic isometric vacuolization, corresponding to a focus of tubules with abundant intracellular viral arrays. Individual viruses averaged 76 µm in diameter and had an envelope studded with crown-like, electron-dense spikes. Vacuoles contained double-membrane vesicles suggestive of partially assembled virus. CONCLUSIONS: The presence of viral particles in the renal tubular epithelium that were morphologically identical to SARS-CoV-2, and with viral arrays and other features of virus assembly, provide evidence of a productive direct infection of the kidney by SARS-CoV-2. This finding offers confirmatory evidence that direct renal infection occurs in the setting of AKI in COVID-19. However, the frequency and clinical significance of direct infection in COVID-19 is unclear. Tubular isometric vacuolization observed with light microscopy, which correlates with double-membrane vesicles containing vacuoles observed with electronic microscopy, may be a useful histologic marker for active SARS-CoV-2 infection in kidney biopsy or autopsy specimens.


Assuntos
Lesão Renal Aguda/complicações , Infecções por Coronavirus/complicações , Túbulos Renais/virologia , Pneumonia Viral/complicações , Lesão Renal Aguda/mortalidade , Aneurisma Dissecante/cirurgia , Autopsia , Betacoronavirus , Infecções por Coronavirus/mortalidade , Células Epiteliais/patologia , Humanos , Túbulos Renais/patologia , Túbulos Renais/ultraestrutura , Masculino , Pessoa de Meia-Idade , Nefrite/fisiopatologia , Pandemias , Pneumonia Viral/mortalidade , Prognóstico , Insuficiência Respiratória , Estudos Retrospectivos
15.
Environ Toxicol ; 35(9): 1007-1014, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32441858

RESUMO

Arecoline, a component of betel nuts, is a known carcinogen that causes oral cancers among those who chew betel nuts. Betel nut chewing is also associated with an increased risk of chronic kidney disease (CKD), but the role of arecoline in this association is unclear. This in vitro study investigates the effects of arecoline on cultured human kidney (HK2) cells. We observed that arecoline had no effect on cell viability but increased cell migration in a dose-dependent manner. Western blot analysis showed that arecoline treatment caused a dose-dependent decrease in E-cadherin expression and dose-dependent increases in N-cadherin, vimentin, α-SMA, and collagen expression; reverse transcriptase-polymerase chain reaction analysis revealed dose-dependent increases in α-SMA and collagen mRNA. Arecoline treatment upregulated the expression of phosphorylated extracellular signal-regulated kinase through epithelial mesenchymal transition and renal fibrosis in HK2 cells. These findings demonstrate that arecoline plays a role in inducing the epithelial mesenchymal transition and fibrogenesis in renal tubule cells and suggest that arecoline promotes the progression of CKD.


Assuntos
Areca/toxicidade , Arecolina/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Areca/química , Caderinas/genética , Caderinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/genética , Fibrose , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Sistema de Sinalização das MAP Quinases/genética , Fosforilação , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Regulação para Cima
17.
PLoS One ; 15(4): e0231662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315336

RESUMO

Early detection of obesity-related glomerulopathy in humans is challenging as it might not be detected by routine biomarkers of kidney function. This study's aim was to use novel kidney biomarkers and contrast-enhanced ultrasound (CEUS) to evaluate the effect of obesity development and weight-loss on kidney function, perfusion, and injury in dogs. Sixteen healthy lean adult beagles were assigned randomly but age-matched to a control group (CG) (n = 8) fed to maintain a lean body weight (BW) for 83 weeks; or to a weight-change group (WCG) (n = 8) fed the same diet to induce obesity (week 0-47), to maintain stable obese weight (week 47-56) and to lose BW (week 56-83). At 8 time points, values of systolic blood pressure (sBP); serum creatinine (sCr); blood urea nitrogen (BUN); serum cystatin C (sCysC); urine protein-to-creatinine ratio (UPC); and urinary biomarkers of glomerular and tubular injury were measured. Glomerular filtration rate (GFR) and renal perfusion using CEUS were assayed (except for week 68). For CEUS, intensity- and time-related parameters representing blood volume and velocity were derived from imaging data, respectively. At 12-22% weight-gain, cortical time-to-peak, representing blood velocity, was shorter in the WCG vs. the CG. After 37% weight-gain, sCysC, UPC, glomerular and tubular biomarkers of injury, urinary immunoglobulin G and urinary neutrophil gelatinase-associated lipocalin, respectively, were higher in the WCG. sBP, sCr, BUN and GFR were not significantly different. After 23% weight-loss, all alterations were attenuated. Early weight-gain in dogs induced renal perfusion changes measured with CEUS, without hyperfiltration, preceding increased urinary protein excretion with potential glomerular and tubular injury. The combined use of routine biomarkers of kidney function, CEUS and site-specific urinary biomarkers might be valuable in assessing kidney health of individuals at risk for obesity-related glomerulopathy in a non-invasive manner.


Assuntos
Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais/metabolismo , Obesidade/metabolismo , Ganho de Peso/genética , Animais , Biomarcadores/urina , Nitrogênio da Ureia Sanguínea , Meios de Contraste/farmacologia , Creatinina/sangue , Modelos Animais de Doenças , Cães , Taxa de Filtração Glomerular , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/urina , Humanos , Glomérulos Renais/diagnóstico por imagem , Glomérulos Renais/lesões , Glomérulos Renais/patologia , Túbulos Renais/diagnóstico por imagem , Túbulos Renais/lesões , Túbulos Renais/patologia , Obesidade/complicações , Obesidade/diagnóstico por imagem , Obesidade/patologia , Ultrassonografia , Sistema Urinário/metabolismo , Sistema Urinário/patologia , Ganho de Peso/fisiologia , Perda de Peso/genética , Perda de Peso/fisiologia
18.
Am J Physiol Renal Physiol ; 318(5): F1167-F1176, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32223312

RESUMO

Cellular senescence, a permanent arrest of cell proliferation, is characterized by a senescence-associated secretory phenotype (SASP), which reinforces senescence and exerts noxious effects on adjacent cells. Recent studies have suggested that transplanting small numbers of senescent cells suffices to provoke tissue inflammation. We hypothesized that senescent cells can directly augment renal injury. Primary scattered tubular-like cells (STCs) acquired from pig kidneys were irradiated by 10 Gy of cesium radiation, and 3 wk later cells were characterized for levels of senescence and SASP markers. Control or senescent STCs were then prelabeled and injected (5 × 105 cells) into the aorta of C57BL/6J mice. Four weeks later, renal oxygenation was studied in vivo using 16.4-T magnetic resonance imaging and function by plasma creatinine level. Renal markers of SASP, fibrosis, and microvascular density were evaluated ex vivo. Per flow cytometry, irradiation induced senescence in 80-99% of STCs, which showed increased gene expression of senescence and SASP markers, senescence-associated ß-galactosidase staining, and cytokine levels (especially IL-6) secreted in conditioned medium. Four weeks after injection, cells were detected engrafted in the mouse kidneys with no evidence for rejection. Plasma creatinine and renal tissue hypoxia increased in senescent compared with control cells. Senescent kidneys were more fibrotic, with fewer CD31+ endothelial cells, and showed upregulation of IL-6 gene expression. Therefore, exogenously delivered senescent renal STCs directly injure healthy mouse kidneys. Additional studies are needed to determine the role of endogenous cellular senescence in the pathogenesis of kidney injury and evaluate the utility of senolytic therapy.


Assuntos
Proliferação de Células , Senescência Celular , Túbulos Renais/transplante , Rim/cirurgia , Animais , Proliferação de Células/efeitos da radiação , Células Cultivadas , Senescência Celular/efeitos da radiação , Feminino , Fibrose , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Túbulos Renais/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Sus scrofa , Transplante Heterólogo
20.
Curr Pharm Biotechnol ; 21(12): 1204-1212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32297575

RESUMO

OBJECTIVES: To investigate the effect of Danggui-Shaoyao-San (DSS)-containing serum on the renal tubular Epithelial-Mesenchymal Transition (EMT) of Diabetic Nephropathy (DN) in high glucose- induced HK-2 cells and its mechanism. METHODS: 20 rats were randomly divided into four groups: blank control group, DSS low dose group (DSS-L), DSS middle dose group (DSS-M), and DSS high dose group (DSS-H). DSS was administrated to the corresponding group (7g/kg/d, 14g/kg/d and 21g/kg/d) for 7 consecutive days, and the same volume of saline was given to the blank control group by gavage. The rat drug-containing serum was successfully prepared. HK-2 cells were divided into five groups: blank control group, model group, DSS-L, DSS-M, DSS-H, according to the corresponding drug and dose of each treatment group. Protein and mRNA levels of Jagged1, Notch1, Hes5, Notch Intracellular Domain (NICD), E-cadherin, alpha- Smooth Muscle Actin (α-SMA) and vimentin at 24h, 48h and 72h were detected by Western Blot and RT-qPCR. RESULTS: The protein and mRNA levels of Jagged1, Notch1, Hes5, NICD, α-SMA and vimentin in the treatment groups were remarkably decreased compared with the model group (P<0.05), and the protein and mRNA levels of E-cadherin were notably increased (P<0.05) by Western Blot and RT-qPCR. CONCLUSION: Our results demonstrated that DSS could prevent DN by ameliorating renal tubular EMT through inhibition of the Notch signaling pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Receptor Notch1/antagonistas & inibidores , Actinas/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Células Epiteliais/metabolismo , Humanos , Proteína Jagged-1/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Ratos Sprague-Dawley , Soro/química , Transdução de Sinais
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