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1.
Nat Commun ; 11(1): 4467, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948751

RESUMO

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.


Assuntos
Fibrose/genética , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Nefropatias/genética , Idoso , Animais , Apoptose , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Nefropatias Diabéticas , Modelos Animais de Doenças , Feminino , Fibrose/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Inflamação , Rim/lesões , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Supressora de Tumor p53/metabolismo
2.
Ecotoxicol Environ Saf ; 204: 111061, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32750588

RESUMO

The use of hexavalent chromium (Cr(VI)) in many industrial processes has resulted in serious environmental pollution problems. Cr(VI) causes organ toxicity in animals after ingestion or inhalation. However, the exact mechanism by which Cr(VI) produces kidney damage remains elusive. Herein, we investigated whether Cr(VI)-induced kidney damage is related to the disorder of mitochondrial dynamics. In this study, 28 male rats were divided into four groups and intraperitoneally injected with 0, 2, 4, and 6 mg/kg body weight potassium dichromate for 5 weeks. Experiment included analysis of renal histopathology and ultrastructure, determination of biochemical indicators, and measurement of related protein content. The results showed that Cr(VI) induced kidney injury through promotion of oxidative stress, apoptosis, and disorder of mitochondrial dynamics in a dose-dependent manner. The protein levels of the silent information regulator two ortholog 1 (Sirt1), peroxisome proliferation-activated receptor-g coactivator-1a (PGC-1a), and autophagy-related proteins were significantly decreased after Cr(VI) exposure. These findings suggest that Cr(VI) leads to the disorder of mitochondrial dynamics by inhibiting the Sirt1/PGC-1a pathway, which leads to renal apoptosis and autophagy in rats.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cromo/toxicidade , Rim/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Rim/metabolismo , Rim/ultraestrutura , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Dicromato de Potássio/toxicidade , Ratos , Ratos Wistar
3.
J Med Life ; 13(2): 116-118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728402

RESUMO

The role of the renin-angiotensin system in hypertension and end-organ damage has long been recognized. Angiotensin l converting enzyme inhibitors are superior to other antihypertensive agents in protecting the kidney against progressive deterioration, even in normotensive persons. Likewise, angiotensin II type 1 receptor antagonists improve or even reverse glomerulosclerosis in rat animal models. These findings suggest that Angiotensin II has nonhemodynamic effects in progressive renal disease. The renin-angiotensin system is now recognized to be linked to the induction of plasminogen activator-inhibitor-1, possibly via the AT4 receptor, thus promoting both thrombosis and fibrosis. Interactions of the renin-angiotensin system with aldosterone and bradykinin may impact both blood pressure and tissue injury. The beneficial effect on renal fibrosis of inhibiting the renin-angiotensin system likely reflects the central role that angiotensin has in regulating renal function and structure by its various actions. This article explores the renin-angiotensin-aldosterone system with plasminogen activator-inhibitor-1 interaction and the potential significance of these interactions in the pathogenesis of progressive renal disease and remodeling of renal sclerosis.


Assuntos
Nefropatias/patologia , Envelhecimento/patologia , Aldosterona/metabolismo , Angiotensinas/metabolismo , Animais , Humanos , Indução de Remissão , Sistema Renina-Angiotensina
4.
Lancet ; 396(10246): 277-287, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711803

RESUMO

Acute and chronic kidney disease encompasses a complex set of diseases that can both lead to, and result from, cancer. In particular, kidney disease can arise from the use of chemotherapeutic agents. Many of the current and newly developed cancer chemotherapeutic agents are nephrotoxic and can promote kidney dysfunction, which frequently manifests during the terminal stages of cancer. Given the link between kidney disease and cancer development and treatment, the aim of this Review is to highlight the importance of multidisciplinary collaboration between oncologists and nephrologists to predict and prevent chemotherapeutic-induced nephrotoxicity. As new therapies are introduced to treat cancer, new renal toxicities require proper diagnosis and management. We anticipate that multidisciplinary collaborations will lead to the development and implementation of guidelines for clinicians to improve the therapeutic management of patients with both cancer and renal impairment.


Assuntos
Antineoplásicos/efeitos adversos , Nefropatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Lesão Renal Aguda/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Humanos , Comunicação Interdisciplinar , Nefropatias/patologia , Nefrologistas , Oncologistas , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia
5.
J Am Soc Nephrol ; 31(9): 1959-1968, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32680910

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury by a variety of mechanisms. To date, pathologic analyses have been limited to patient reports and autopsy series. METHODS: We evaluated biopsy samples of native and allograft kidneys from patients with COVID-19 at a single center in New York City between March and June of 2020. We also used immunohistochemistry, in situ hybridization, and electron microscopy to examine this tissue for presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: The study group included 17 patients with COVID-19 (12 men, 12 black; median age of 54 years). Sixteen patients had comorbidities, including hypertension, obesity, diabetes, malignancy, or a kidney or heart allograft. Nine patients developed COVID-19 pneumonia. Fifteen patients (88%) presented with AKI; nine had nephrotic-range proteinuria. Among 14 patients with a native kidney biopsy, 5 were diagnosed with collapsing glomerulopathy, 1 was diagnosed with minimal change disease, 2 were diagnosed with membranous glomerulopathy, 1 was diagnosed with crescentic transformation of lupus nephritis, 1 was diagnosed with anti-GBM nephritis, and 4 were diagnosed with isolated acute tubular injury. The three allograft specimens showed grade 2A acute T cell-mediated rejection, cortical infarction, or acute tubular injury. Genotyping of three patients with collapsing glomerulopathy and the patient with minimal change disease revealed that all four patients had APOL1 high-risk gene variants. We found no definitive evidence of SARS-CoV-2 in kidney cells. Biopsy diagnosis informed treatment and prognosis in all patients. CONCLUSIONS: Patients with COVID-19 develop a wide spectrum of glomerular and tubular diseases. Our findings provide evidence against direct viral infection of the kidneys as the major pathomechanism for COVID-19-related kidney injury and implicate cytokine-mediated effects and heightened adaptive immune responses.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Rim/patologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Biópsia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Feminino , Humanos , Rim/ultraestrutura , Rim/virologia , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia
6.
Life Sci ; 257: 118138, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32712298

RESUMO

AIMS: Hypertension is a relevant sex and sex hormones-dependent risk factor where the cardiovascular and renal health of the population are concerned. Men experience greater losses of renal function (RF) than women, but the mechanisms remain somewhat unclear. Our goal was to evaluate the relationship between oxidative stress (OS), angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activities and RF in male and female SHR. MAIN METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were submitted to either castration or SHAM surgery and divided into 4 groups, SHAM or Castrated (CAST) males or females. After 51 days we evaluated RF (inulin and sodium para-aminohippurate), ACE and ACE2 activities (fluorimetry), OS (flow cytometry), collagen deposition (picrosirius red) and protein expression (western blot). KEY FINDINGS: Males presented lower RF than females and castration impaired this parameter in both groups. Sexual dimorphism was not observed regarding OS and inflammation; however, castration increased this parameter more severely in males than in females. SHAM males exhibited higher collagen deposition than females, though castration increased it in both sexes, eliminating the difference. We found sexual dimorphism regarding renal ACE and ACE2 activities, which were lower in males than in females. Although castration did not alter ACE activity, it reduced ACE2 activity in females and increased it in males. SIGNIFICANCE: These results indicate that sex hormones affect RF in SHR. As alterations in the oxidative system were capable of promoting podocyte injury, inflammation, and collagen deposition, we put forward that these effects are differently modulated by ACE and ACE2.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Nefropatias/etiologia , Estresse Oxidativo , Peptidil Dipeptidase A/metabolismo , Ratos Endogâmicos SHR/metabolismo , Animais , Western Blotting , Colágeno/metabolismo , Feminino , Rim/enzimologia , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Masculino , Orquiectomia , Ovariectomia , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos SHR/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fatores Sexuais
7.
Autoimmun Rev ; 19(9): 102622, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32663622

RESUMO

Immunoglobulin light chain amyloidosis is a rare systemic disease caused by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils resulting in irreversible damage of vital organs. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells are undoubtedly involved in monoclonal LC production. We are reporting favorable effects on AL amyloidosis patients with renal involvement using the anti-CD38 monoclonal antibody Daratumumab. We speculate that research for the near future should be devoted to design similar therapeutic approaches for other diseases attributable to a plasma cell dyscrasia.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Nefropatias/tratamento farmacológico , Paraproteinemias/tratamento farmacológico , Humanos , Cadeias Leves de Imunoglobulina , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Rim/patologia , Nefropatias/patologia , Paraproteinemias/patologia
9.
J Pharmacol Sci ; 143(4): 281-289, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32513569

RESUMO

FoxM1 is a transcriptional regulator involved in tumor development, pulmonary fibrosis, and cardiac fibrosis. However, its role in renal interstitial fibrosis (RIF) has yet to be elucidated. We established a TGF-ß1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro and a unilateral ureteral obstruction (UUO)-induced rat RIF model in vivo. FoxM1 inhibition was achieved by siRNA interference in vitro and by injecting thiostrepton into UUO-induced RIF rats in vivo. The degree of renal damage and fibrosis were determined by histological assessment via hematoxylin and eosin (H&E) staining. Immunohistochemistry, western blots, and qPCR were used to determine the expression levels of FoxM1, Collagen I, E-cadherin, α-SMA, and Snail1. Our results showed that FoxM1 inhibition could ameliorate RIF and reduce the deposition of Collagen I. H&E staining revealed that renal structural damage, inflammatory cell infiltration, and ECM deposition were significantly attenuated by thiostrepton treatment in the UUO rats. Furthermore, FoxM1 downregulation significantly suppressed epithelial-to-mesenchymal transition, as evidenced by decreased protein and mRNA expression levels of α-SMA and Snail1 and a significant increase in protein and mRNA expression levels of E-cadherin. Collectively, these results suggested that FoxM1 inhibition could be a novel therapeutic strategy for the treatment of RIF.


Assuntos
Transição Epitelial-Mesenquimal , Matriz Extracelular/patologia , Proteína Forkhead Box M1/genética , Inativação Gênica , Nefropatias/genética , Rim/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibrose , Humanos , Nefropatias/patologia , Nefropatias/terapia , Masculino , Ratos
10.
Vet Q ; 40(1): 190-197, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32543343

RESUMO

Background: The natural MERS-CoV infection in dromedary camels is understudied. Recent experimental studies showed no obvious clinical signs in the infected dromedary camels.Aim: To study the pathological changes associated with natural MERS-CoV infection in dromedary camels.Methods: Tissues from three MERS-CoV positive animals as well as two negative animals were collected and examined for the presence of pathological changes. The screening of the animals was carried out first by the rapid agglutination test and then confirmed by the RT-PCR. The selected animals ranged from six to twelve months in age. The sensitivity of the latter technique was much higher in the detection of MERS-CoV than the Rapid test (14 out of 75 animals positive or 18% versus 31 out of 75 positive or 41%).Results: MERS-CoV induced marked desquamation of the respiratory epithelium accompanied by lamina propria and submucosal mononuclear cells infiltration, epithelial hyperplasia in the respiratory tract, and interstitial pneumonia. Ciliary cell loss was seen in the trachea and turbinate. In addition, degeneration of glomerular capillaries with the complete destruction of glomerular tufts that were replaced with fibrinous exudate in renal corpuscles in the renal cortex were noticed. Expression of the MERS-CoV-S1 and MERS-CoV-N proteins was revealed in respiratory tract, and kidneys.Conclusion: To our knowledge, this is the first study describing the pathological changes of MERS-CoV infection in dromedary camels under natural conditions. In contrast to experimental infection in case of spontaneous infection interstitial pneumonea is evident at least in some affected animals.


Assuntos
Camelus/virologia , Infecções por Coronavirus/veterinária , Doenças Pulmonares Intersticiais/veterinária , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Animais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Nefropatias/patologia , Nefropatias/veterinária , Nefropatias/virologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Masculino , Arábia Saudita , Proteínas Virais/análise
11.
Proc Natl Acad Sci U S A ; 117(27): 15862-15873, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561647

RESUMO

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.


Assuntos
Albuminúria/metabolismo , Nefropatias/metabolismo , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Transdução de Sinais/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas , Modelos Animais de Doenças , Regulação para Baixo , Doxorrubicina/farmacologia , Humanos , Insulina/metabolismo , Nefropatias/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/urina , Podócitos/metabolismo , Proteômica , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Am J Physiol Renal Physiol ; 319(1): F93-F105, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475133

RESUMO

The long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to promote liver fibrosis progression. However, its molecular mechanism in renal fibrosis was not elucidated. In the present study, an in vitro model of renal fibrosis was established with HK-2 and HKC-8 cells treated with transforming growth factor-ß1. C57BL/6 mice were used for the in vivo model with unilateral ureteral obstruction. Our results indicated that NEAT1 and collagen type I levels were significantly upregulated, whereas miR-129 was obviously downregulated, in the progression of renal fibrosis. Meanwhile, NEAT1 knockdown or miR-129 overexpression inhibited collagen type I deposition, the epithelial-mesenchymal transition process, and the inflammation response to suppress renal fibrosis. NEAT1 directly targeted miR-129, and miR-129 directly bound to collagen type I. Downregulation of miR-129 reversed inhibition of renal fibrosis induced by NEAT1 silencing, and upregulation of collagen type I also reversed inhibition of renal fibrosis caused by miR-129 overexpression. NEAT1 knockdown alleviated renal fibrosis in mice subjected to unilateral ureteral obstruction. In conclusion, NEAT1 sponged miR-129 to modulate the epithelial-mesenchymal transition process and inflammation response of renal fibrosis by regulation of collagen type I. Our study indicates a novel role in the regulation of renal fibrosis and provides a new potential treatment target for renal fibrosis.


Assuntos
Colágeno Tipo I/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Creatinina/sangue , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta1/farmacologia
13.
Clin Sci (Lond) ; 134(11): 1245-1253, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32501496

RESUMO

Chronic kidney disease (CKD) substantially reduces quality of life and leads to premature death for thousands of people each year. Dialysis and kidney organ transplants remain prevalent therapeutic avenues but carry significant medical, economic and social burden. Podocytes are responsible for blood filtration selectivity in the kidney, where they extend a network of foot processes (FPs) from their cell bodies which surround endothelial cells and interdigitate with those on neighbouring podocytes to form narrow slit diaphragms (SDs). During aging, some podocytes are lost naturally but accelerated podocyte loss is a hallmark of CKD. Insights into the origin of degenerative podocyte loss will help answer important questions about kidney function and lead to substantial health benefits. Here, approaches that uncover insights into podocyte mechanobiology are reviewed, both those that interrogate the biophysical properties of podocytes and how the external physical environment affects podocyte behaviour, and also those that interrogate the biophysical effects that podocytes exert on their surroundings.


Assuntos
Biofísica , Saúde , Nefropatias/patologia , Podócitos/patologia , Animais , Fenômenos Biomecânicos , Humanos , Estresse Mecânico
14.
Ren Fail ; 42(1): 513-522, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32441195

RESUMO

Objective: To investigate the way that miR-136 regulated spleen tyrosine kinase (SYK) and transforming growth factor-ß1 (TGF-ß1)/Smad3 signaling pathways on renal fibrosis.Methods: 100 male SD (Sprague-Dawley) rats were randomly divided into diabetic nephropathy (DN) group, normal control (NC) group, miR-136 mimics group, and control group. The renal fibrosis model of diabetic rats was established by streptozotocin (STZ) method. NRK-52E cells were transfected into six groups: HG group, HG + miR-136 group, HG + miR-NC group, miR-136 + SYK group, miR-136 + NC group, and control group. Histopathological examination, the expressions of miR-136 and SYK mRNA, the expression of mTOR, blood glucose, urine protein, body weight, creatinine level, blood urea nitrogen (BUN), and KW/BW were detected in each group. Transfection efficiency, the targeted binding, and regulation between miR-136 and SYK, as well as the expression level of related inflammatory factors, the expression levels of SYK, E-Cad (E-cadherin), Vimentin, Collagen I, α-smooth muscle actin (α-SMA), and vascular endothelial growth factor A (VEGFA) were detected.Results: It was shown that the expression level of miR-136 in DN group significantly decreased. The blood glucose and urine protein concentrations in the DN group and miR-136 mimics group significantly increased and the body weight was decreased, but the blood glucose concentration in the miR-136 mimics group increased with time. The prolongation of the decline significantly decreased, and the growth rate of urinary protein reduced. Creatinine, BUN, and the kidney weight to body weight ratio (KW/BW) in DN group increased significantly. Cell culture results showed that SYK was a target gene of miR-136 and miR-136/SYK-mediated renal fibrosis by activating TGF-ß1/Smad3 signal.Conclusion: SYK activates TGF-ß1/Smad3 signaling, while miR-136 inhibits TGF-ß1/Smad3 signaling mediating tubular epithelial cell fibrosis by down-regulating SYK.


Assuntos
Nefropatias/metabolismo , Nefropatias/patologia , MicroRNAs/genética , Transdução de Sinais , Quinase Syk/metabolismo , Animais , Linhagem Celular , Regulação para Baixo , Fibrose/genética , Fibrose/metabolismo , Nefropatias/genética , Masculino , Ratos , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Quinase Syk/genética , Fator de Crescimento Transformador beta1/metabolismo
16.
Life Sci ; 255: 117845, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470449

RESUMO

AIMS: Renal fibrosis is the typical manifestation of progressive kidney disease and causes a severe threat to human health. Surging evidence has illustrated that miRNA plays a core role in the genesis and development of kidney fibrosis. MiR-542-3p has been testified to function as a facilitator in hepatic stellate cell activation and fibrosis. The purpose of study is to investigate the potential of miR-542-3p in renal tubulointerstitial fibrosis. MATERIALS AND METHODS: In this study, to establish renal fibrosis model in vivo and in vitro, we first conducted unilateral ureteral obstruction (UUO) on rats and high glucose (HG) treatment on the HK-2 cells. Histological and western blot analyses were utilized for assessment of renal fibrosis model. Luciferase reporter assay was carried out to explore the regulatory mechanism underlying miR-542-3p in renal fibrosis. KEY FINDINGS: MiR-542-3p was found to be highly expressed in renal fibrosis. Functional experiments revealed that overexpression of miR-542-3p accelerated the deterioration of kidney fibrosis and inhibition of miR-542-3p led to the opposite result. Through the aid of bioinformatics tool, the speculated miR-542-3p binding sites were uncovered in the 3'UTR of argonaute RISC component 1 (AGO1). Mechanism study elucidated that AGO1 was a direct target of miR-542-3p. Lastly, our findings suggested that miR-542-3p played a promoting role in renal fibrosis via repression of AGO1. SIGNIFICANCE: We justified that miR-542-3p induced kidney fibrogenesis both in vivo and in vitro through targeting AGO1, unveiling that miR-542-3p might be a promising option for the treatment of patients with renal fibrosis.


Assuntos
Proteínas Argonauta/genética , Fatores de Iniciação em Eucariotos/genética , Nefropatias/patologia , Rim/patologia , MicroRNAs/genética , Animais , Sítios de Ligação , Linhagem Celular , Biologia Computacional , Modelos Animais de Doenças , Fibrose , Glucose/metabolismo , Humanos , Nefropatias/genética , Masculino , Ratos , Ratos Sprague-Dawley , Obstrução Ureteral/patologia
17.
Phytomedicine ; 72: 153232, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32460034

RESUMO

BACKGROUND: In chronic kidney disease, although fibrosis prevention is beneficial, few interventions are available that specifically target fibrogenesis. Poricoic acid A (PAA) isolated from Poria cocos exhibits anti-fibrotic effects in the kidney, however the underlying mechanisms remain obscure. PURPOSE: We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis. STUDY DESIGN: Unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (Nx) animal models and TGF-ß1-induced renal fibroblasts (NRK-49F) were used to investigate the anti-fibrotic activity of PAA and its underlying mechanisms. METHODS: Western blots, qRT-PCR, immunofluorescence staining, co-immunoprecipitation and molecular docking methods were used. Knock-down and knock-in of adenosine monophosphate-activated protein kinase (AMPK) in the UUO model and cultured NRK-49F cells were employed to verify the mechanisms of action of PAA. RESULTS: PAA improved renal function and alleviated fibrosis by stimulating AMPK and inhibiting Smad3 specifically in Nx and UUO models. Reduced AMPK activity was associated with Smad3 induction, fibroblast activation, and the accumulation and aberrant remodelling of extracellular matrix (ECM) in human renal puncture samples and cultured NRK-49F cells. PAA stimulated AMPK activity and decreased fibrosis in a dose-dependent manner, thus showing that AMPK was essential for PAA to exert its anti-fibrotic effects. AMPK deficiency reduced the anti-fibrotic effects of PAA, while AMPK overexpression enhanced its effect. CONCLUSION: PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Matriz Extracelular/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Rim/patologia , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/genética , Animais , Estudos de Casos e Controles , Linhagem Celular , Relação Dose-Resposta a Droga , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
18.
Braz J Med Biol Res ; 53(6): e8625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428129

RESUMO

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min-1·(1.73 m2)-1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min-1·(1.73 m2)-1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.


Assuntos
Amiloide/fisiologia , Amiloidose/patologia , Taxa de Filtração Glomerular , Nefropatias/patologia , Rim/patologia , Adulto , Idoso , Amiloidose/fisiopatologia , Biópsia , Feminino , Humanos , Rim/fisiopatologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
PLoS One ; 15(5): e0233109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437461

RESUMO

Normalisation to standard reference gene(s) is essential for quantitative real-time polymerase chain reaction (RT-qPCR) to obtain reproducible and comparable results of a gene of interest (GOI) between subjects and under varying experimental conditions. There is limited evidence to support selection of the commonly used reference genes in rat ischaemic and toxicological kidney models. Employing these models, we determined the most stable reference genes by comparing 4 standard methods (NormFinder, qBase+, BestKeeper and comparative ΔCq) and developed a new 3-way linear mixed-effects model for evaluation of reference gene stability. This new technique utilises the intra-class correlation coefficient as the stability measure for multiple continuous and categorical covariates when determining the optimum normalisation factor. The model also determines confidence intervals for each candidate normalisation gene to facilitate selection and allow sample size calculation for designing experiments to identify reference genes. Of the 10 candidate reference genes tested, the geometric mean of polyadenylate-binding nuclear protein 1 (PABPN1) and beta-actin (ACTB) was the most stable reference combination. In contrast, commonly used ribosomal 18S and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were the most unstable. We compared the use of PABPN1×ACTB and 2 commonly used genes 18S and GAPDH on the expression of 4 genes of interest know to vary after renal injury and expressed by different kidney cell types (KIM-1, HIF1α, TGFß1 and PECAM1). The less stable reference genes gave varying patterns of GOI expression in contrast to the use of the least unstable reference PABPN1×ACTB combination; this improved detection of differences in gene expression between experimental groups. Reduced within-group variation of the now more accurately normalised GOI may allow for reduced experimental group size particularly for comparison between various models. This objective selection of stable reference genes increased the reliability of comparisons within and between experimental groups.


Assuntos
Regulação da Expressão Gênica , Isquemia/metabolismo , Nefropatias/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/normas , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Actinas/biossíntese , Animais , Isquemia/patologia , Rim/patologia , Nefropatias/patologia , Proteína I de Ligação a Poli(A)/biossíntese , RNA Ribossômico 18S/biossíntese , Ratos , Padrões de Referência
20.
Cardiovasc Pathol ; 48: 107218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32388447

RESUMO

Cardiac amyloid A (AA) amyloidosis is rare. We present the case of a 72-year-old woman with obstructive hypertrophic cardiomyopathy (HCM) and biopsy-proven renal AA amyloidosis whose dyspnea and exercise intolerance had worsened over the previous year. Her AA amyloidosis was suspected to be secondary to chronic diverticulitis for which she had undergone hemicolectomy and sigmoidectomy 3 years prior. Echocardiographic findings were consistent with worsening left ventricular outflow tract obstruction at rest. Cardiac magnetic resonance imaging revealed patchy areas of midwall late gadolinium enhancement. Right ventricular endomyocardial biopsy did not reveal amyloid deposition, and cardiac technetium-99m pyrophosphate scintigraphy did not suggest transthyretin amyloidosis. The patient underwent septal myectomy with resection of an accessory papillary muscle. Pathological examination of the myectomy specimen was consistent with HCM. In addition, there was a thick layer of diffuse endocardial and vascular amyloid deposition that was identified as AA type by laser-microdissection with liquid chromatography-coupled tandem-mass spectrometry. This case report highlights the presence of 2 distinct disease processes occurring simultaneously and the importance of tissue diagnosis of AA amyloidosis, a condition that is not commonly associated with HCM.


Assuntos
Amiloidose/complicações , Cardiomiopatia Hipertrófica/complicações , Insuficiência Cardíaca/etiologia , Nefropatias/complicações , Miocárdio/patologia , Obstrução do Fluxo Ventricular Externo/etiologia , Idoso , Amiloidose/metabolismo , Amiloidose/patologia , Amiloidose/fisiopatologia , Procedimentos Cirúrgicos Cardíacos , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Miocárdio/metabolismo , Proteína Amiloide A Sérica/metabolismo , Resultado do Tratamento , Função Ventricular Esquerda , Obstrução do Fluxo Ventricular Externo/metabolismo , Obstrução do Fluxo Ventricular Externo/patologia , Obstrução do Fluxo Ventricular Externo/fisiopatologia
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