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1.
Adv Exp Med Biol ; 1255: 195-202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949401

RESUMO

In this chapter, we discussed some of the specific uses of scRNA-seq in exploring viral infections and diseases of the kidney and pancreas. This review, however, is by no means exhaustive, and indeed this technology has advanced the study of pulmonary and cardiac diseases, transplant immunology, cancer, and many others as well. Nevertheless, the above reviewed studies do illustrate the utility and resolution of scRNA-seq in understanding exact cellular compositions, discovering heterogeneity within cellular expression patterns, and uncovering clues that may eventually lead to the development of more targeted and personalized therapies. Additionally, the increasing availability of whole tissue cellular atlases in both health and disease as a result of scRNA-seq studies provides an important resource to better understand complicated molecular signaling patterns and events that are similar and different between human diseases.


Assuntos
Nefropatias/genética , Pancreatopatias/genética , Análise de Sequência de RNA , Análise de Célula Única , Viroses/genética , Humanos
2.
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
3.
Am J Physiol Cell Physiol ; 319(2): C316-C320, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32639871

RESUMO

Pulmonary surfactant is a heterogeneous active surface complex made up of lipids and proteins. The major glycoprotein in surfactant is surfactant protein A (SP-A), which is released into the alveolar lumen from cytoplasmic lamellar bodies in type II alveolar epithelial cells. SP-A is involved in phospholipid absorption. SP-A together with other surfactant proteins and phospholipids prevent alveolar collapse during respiration by decreasing the surface tension of the air-liquid interface. Additionally, SP-A interacts with pathogens to prevent their propagation and regulate host immune responses. Studies in human and animal models have shown that deficiencies or mutations in surfactant components result in various lung or kidney pathologies, suggesting a role for SP-A in the development of lung and kidney diseases. In this mini-review, we discuss the current understanding of SP-A functions, recent findings of its dysfunction in specific lung and kidney pathologies, and how SP-A has been used as a biomarker to detect the outcome of lung diseases.


Assuntos
Nefropatias/genética , Pneumopatias/genética , Alvéolos Pulmonares/metabolismo , Proteína A Associada a Surfactante Pulmonar/genética , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Citoplasma/genética , Citoplasma/metabolismo , Progressão da Doença , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/patologia , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , Alvéolos Pulmonares/patologia , Surfactantes Pulmonares/metabolismo
4.
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
5.
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
6.
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
7.
Nat Commun ; 11(1): 1943, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327648

RESUMO

Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-ß1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-ß1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.


Assuntos
Nefropatias/patologia , Rim/patologia , alfa-Sinucleína/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Rim/metabolismo , Nefropatias/genética , Nefropatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Vimentina/genética , Vimentina/metabolismo , alfa-Sinucleína/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Clín. investig. arterioscler. (Ed. impr.) ; 32(2): 70-78, mar.-abr. 2020. ilus
Artigo em Inglês | IBECS | ID: ibc-187150

RESUMO

The elevation of blood pressure produces specific organic lesions, including kidney and cardiac damage. On the other hand, cardiovascular disease usually leads to the development of hypertension. Thus, hypertension could be both a cause and a consequence of cardiovascular disease. Previous studies linked the lack of nitric oxide to cardiovascular abnormalities, including hypertension, arteriosclerosis, myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced endothelium-derived hyperpolarizing factor responses, with shorter survival. The lack of this gas also leads to renal/cardiac abnormalities.It is widely known that nephrogenic deficiency is a risk factor for kidney disease. Besides, recent evidence suggests that alterations in WT-1, a key nephrogenic factor, could contribute to the development of hypertension. Moreover, some genes involved in the development of hypertension depend on WT-1.This knowledge makes it essential to investigate and understand the mechanisms regulating the expression of these genes during renal/cardiac development, and hypertension. As a consequence, the most in-depth knowledge of the complex aetiopathogenic mechanism responsible for the hypertensive disease will allow us to propose novel therapeutic tools


La hipertensión produce lesiones orgánicas específicas como daño renal/cardíaco, mientras que la enfermedad cardiovascular generalmente conduce a la hipertensión. Por ello, la hipertensión sería tanto una causa como una consecuencia de la enfermedad cardiovascular. Estudios previos refieren falta de óxido nítrico con anomalías cardiovasculares como hipertensión y reducción de las respuestas del factor hiperpolarizante derivado del endotelio. La falta de este gas también conduce a anomalías renales/cardíacas. Además, la deficiencia nefrogénicaes un factor de riesgo para la enfermedad renal. Así, alteraciones en WT-1, un factor nefrógeno clave, podrían contribuir al desarrollo de hipertensión. Finalmente, el conocimiento más profundo del complejo mecanismo etiopatogénico responsable de la enfermedad hipertensiva nos permitirá proponer nuevas herramientas terapéuticas


Assuntos
Humanos , Hipertensão/genética , Expressão Gênica/genética , Proteínas WT1/genética , Nefropatias/genética , Doenças Cardiovasculares/genética , Óxido Nítrico/genética
10.
Adv Exp Med Biol ; 1236: 109-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304071

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects, which cause the majority of chronic kidney diseases in children. CAKUT covers a wide range of malformations that derive from deficiencies in embryonic kidney and lower urinary tract development, including renal aplasia, hypodysplasia, hypoplasia, ectopia, and different forms of ureter abnormalities. The majority of the genetic causes of CAKUT remain unknown. Research on mutant mice has identified multiple genes that critically regulate renal differentiation. The data generated from this research have served as an excellent resource to identify the genetic bases of human kidney defects and have led to significantly improved diagnostics. Furthermore, genetic data from human CAKUT studies have also revealed novel genes regulating kidney differentiation.


Assuntos
Modelos Animais de Doenças , Nefropatias/congênito , Rim/anormalidades , Sistema Urinário/anormalidades , Animais , Doença Crônica , Humanos , Nefropatias/diagnóstico , Nefropatias/genética , Camundongos
11.
Curr Med Sci ; 40(1): 48-54, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166664

RESUMO

C1q/TNF-related protein 1 (CTRP1), a conserved protein of the C1q family, plays a key role in cardiovascular and metabolic diseases. However, the role of CTRP1 in renal injury is unclear. The purpose of this study is to explore the role of CTRP1 in unilateral ureteral obstruction (UUO)-induced renal fibrosis and to elucidate the underlying mechanism. Using gene delivery system, CTRP1 was overexpressed in the kidney, then the mice were operated to induce UUO model after adenovirus transfection. It was found that the expression of CTRP1 in the renal tissue was decreased in mice after UUO. CTRP1 overexpression decreased the kidney function and kidney weight index. Moreover, CTRP1 reduced oxidative stress and renal collagen deposition in vivo. As expected, we found that CTRP1 activated AMP-activated kinase (AMPK) and decreased NOX4 expression, while silencing AMPKα1 abolished the protective effects of CTRP1 overexpression in mice after UUO. In conclusion, CTRP1 may protect against UUO-induced renal injury via AMPK/NOX4 signaling. Our results indicate that CTRP1 exhibits potential effects to treat renal fibrosis caused by UUO.


Assuntos
Adipocinas/genética , Nefropatias/genética , Rim/patologia , NADPH Oxidase 4/metabolismo , Obstrução Ureteral/cirurgia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrose , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Testes de Função Renal , Masculino , Camundongos , Tamanho do Órgão , Estresse Oxidativo , Transdução de Sinais
12.
Life Sci ; 252: 117589, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32220622

RESUMO

BACKGROUND: Renal fibrosis is the characteristic of all kinds of chronic kidney diseases (CKDs). Fascin-1 plays an important role in tumor development, but the roles of fascin-1 in renal fibrosis have not been studied. Here, we explored the role of fascin-1 in renal fibrosis and the potential mechanisms. METHODS: Kidney unilateral ureteral obstruction (UUO) mouse model was used as an in vivo model, and proximal tubule epithelial cell lines treated with TGF-ß1 were used as in vitro model of renal fibrosis. Cell transfection was performed to manipulate the expression of miR-200b/c, fascin-1 and CD44. Western blotting, qRT-PCR, immunohistochemistry or immunofluorescence assays were used to measure levels of miR-200b/c, fascin-1, CD44, and fibrosis and EMT-related markers. H&E and Masson stainings were used to examine the degree of injury and fibrosis in kidneys. Dual luciferase assay was used to examine the interaction between miR-200b/c family and fascin-1. RESULTS: Fascin-1 and CD44 levels were both significantly up-regulated while miR-200b/c family was reduced in models of renal fibrosis. Furthermore, overexpression of miR-200b/c family and inhibition of fascin-1 or CD44 ameliorated renal fibrosis through suppressing EMT process. Mechanistically, miR-200b/c family directly and negatively regulated the expression of fascin-1. Overexpression of fascin-1 could reverse the effects of miR-200b/c family on renal fibrosis, and fascin-1 regulated renal fibrosis by activating CD44. CONCLUSION: Our study is the first to show that fascin-1 plays a critical role in renal fibrosis. MiR-200b/c family could inhibit renal fibrosis through modulating EMT process by directly targeting fascin-1/CD44 axis.


Assuntos
Transição Epitelial-Mesenquimal/genética , Nefropatias/fisiopatologia , MicroRNAs/genética , Proteínas dos Microfilamentos/metabolismo , Receptores Odorantes/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/patologia , Fibrose , Humanos , Receptores de Hialuronatos , Nefropatias/genética , Túbulos Renais Proximais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1/administração & dosagem , Obstrução Ureteral/genética
13.
J Nutr ; 150(5): 1135-1143, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006016

RESUMO

BACKGROUND: Ex vivo studies suggest that increased renal prostanoids can mediate effects of high-protein (HP) compared with low-protein (LP) diets on normal and diseased kidneys. However, a short-term HP feeding study in normal male rats failed to demonstrate higher renal prostanoids in vivo. OBJECTIVES: The aim of the present study was to investigate whether long-term HP feeding alters renal prostanoids in male and female mice, with and without kidney disease. METHODS: Weanling normal mice (CD1) and mice with kidney disease (CD1-pcy/pcy mice) were fed standard diets with normal protein [NP, 20% of energy (%E)] or HP (35%E) for 13 wk. Renal disease was assessed by histomorphometric analysis of cysts and fibrosis, and measurement of serum urea nitrogen (SUN) and creatinine concentrations. Targeted analysis of renal oxylipins was performed by HPLC-MS/MS. RESULTS: The HP diet increased kidney size and water content of normal kidneys, and worsened disease in CD1-pcy/pcy mice as indicated by higher (P < 0.05) kidney weights (8-31%), water content (8-10%), cyst volume (36-60%), fibrous volume (44-53%), and SUN (47-55%). Diseased compared with normal kidneys had higher (P < 0.05) concentrations of 6 of 11 prostanoids and lower (P < 0.05) concentrations of 33 of 54 other oxylipins. This is consistent with previously known effects of dietary HP and disease effects on the kidney. However, the HP diet did not alter renal prostanoids and other renal oxylipins in either normal or diseased kidneys (P < 0.05), despite having the expected physiological effects on normal and diseased kidneys. This study also showed that females have higher concentrations of renal prostanoids [9 of 11 prostanoids higher (P < 0.05) in females], but lower concentrations of other oxylipins [28 of 54 other oxylipins lower (P < 0.05) in females]. CONCLUSIONS: The effects of HP diets on normal and diseased kidneys in CD1 and CD1-pcy/pcy mice are independent of renal oxylipin alterations.


Assuntos
Dieta Rica em Proteínas/efeitos adversos , Nefropatias/genética , Nefropatias/metabolismo , Rim/química , Oxilipinas/análise , Prostaglandinas/análise , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Genótipo , Rim/patologia , Nefropatias/patologia , Doenças Renais Císticas/congênito , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Masculino , Camundongos , Tamanho do Órgão , Prostaglandina-Endoperóxido Sintases/metabolismo , Fatores Sexuais
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 166-169, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034747

RESUMO

OBJECTIVE: To detect variant of APOE gene in a Chinese Tibetan patient with lipoprotein glomerulopathy (LPG) confirmed by renal biopsy and to explore its pathogenesis. METHODS: Clinical and pathological data was collected. DNA was extracted from peripheral blood sample of the patient and subjected to PCR and Sanger sequencing. Pathogenicity of the variant was analyzed by bioinformatics software. RESULTS: Renal biopsy of the patient has confirmed the diagnosis of LPG. DNA sequencing suggested that the patient has carried a heterozygous c.527G>C (p.R176P) variant of the APOE gene (APOE Osaka/Kurashiki). Four cases of LPG have been found to carry the same variant, and the encoded amino acid (p.176R) is highly conserved during evolution. Bioinformatic analysis using SIFT, PolyPhen2 and PANTHER software all predicted the variant to be pathogenic. CONCLUSION: The discovery of author's patient provided further evidence for the pathogenicity of APOE Osaka/Kurashiki and, more importantly, provide new evidence for the multiracial origin of LPG-related APOE variants.


Assuntos
Apolipoproteínas E/genética , Nefropatias/genética , Humanos , Glomérulos Renais , Mutação , Tibet
15.
J Agric Food Chem ; 68(9): 2765-2772, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045244

RESUMO

Fatty acid esters of 3-monochloropropane 1,2-diol (3-MCPD esters) are processing-induced food toxicants, with the kidney as their major target organ. For the first time, this study treated Sprague Dawley (SD) rats with 3-MCPD 1-monooleate at 10 and 100 mg/kg BW/day and 1-monostearate at 15 and 150 mg/kg BW/day for 90 days and examined for their potential semi-long-term nephrotoxicity and the associated molecular mechanisms. No bodyweight difference was observed between groups during the study. Both 3-MCPD 1-monooleate and 1-monostearate resulted in a dose-dependent increase of serum urea creatinine, uric acid and urea nitrogen levels, and histological renal impairment. The proteomic analysis of the kidney samples showed that the 3-MCPD esters deregulated proteins involved in the pathways for ion transportation, apoptosis, the metabolism of xenobiotics, and enzymes related to endogenous biological metabolisms of carbohydrates, amino acids, nitrogen, lipids, fatty acids, and the tricarboxylic acid (TCA) cycle, providing partial explanation for the nephrotoxicity of 3-MCPD esters.


Assuntos
Nefropatias/metabolismo , Rim/efeitos dos fármacos , Estearatos/toxicidade , alfa-Cloridrina/toxicidade , Animais , Creatinina/urina , Ésteres/metabolismo , Ésteres/toxicidade , Humanos , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/urina , Masculino , Proteômica , Ratos , Ratos Sprague-Dawley , Estearatos/química , Estearatos/metabolismo , Ácido Úrico/urina , alfa-Cloridrina/metabolismo
16.
Am J Physiol Renal Physiol ; 318(4): F911-F921, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068459

RESUMO

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.


Assuntos
Tecido Adiposo/metabolismo , Hemodinâmica , Hipertensão/metabolismo , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Metabolismo dos Lipídeos , Mutação , Obesidade/metabolismo , Receptores para Leptina/genética , Circulação Renal , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Quimiocina CXCL16/genética , Quimiocina CXCL16/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Metabolismo dos Lipídeos/genética , Obesidade/genética , Obesidade/patologia , Obesidade/fisiopatologia , Fenótipo , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/fisiopatologia , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta
17.
Int J Mol Sci ; 21(2)2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947599

RESUMO

Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.


Assuntos
Canais de Cloreto/genética , Doença de Dent/genética , Doença de Dent/patologia , Predisposição Genética para Doença , Nefropatias/genética , Nefropatias/patologia , Mutação , Biomarcadores , Biópsia , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Sequenciamento Completo do Exoma
18.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936371

RESUMO

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-ß1/Smad signaling pathway.


Assuntos
Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Sirtuína 3/genética , Fator de Crescimento Transformador beta1/genética , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose/genética , Fibrose/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Nefropatias/genética , Nefropatias/patologia , Lignanas/farmacologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética
19.
Clin Sci (Lond) ; 134(2): 103-122, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31898747

RESUMO

Alcohol consumption causes renal injury and compromises kidney function. The underlying mechanism of the alcoholic kidney disease remains largely unknown. In the present study, an alcoholic renal fibrosis animal model was first employed which mice received liquid diet containing alcohol for 4 to 12 weeks. The Masson's Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model that was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes (collagen I and α-SMA). In vitro analysis also confirmed that alcohol significantly induced fibrotic response (collagen I and α-SMA) in HK2 tubular epithelial cells. Importantly, both in vivo and in vitro studies showed alcohol treatments decreased Smad7 and activated Smad3. We further determined how the alcohol affected the balance of Smad7 (inhibitory Smad) and Smad3 (regulatory Smad). Genome-wide methylation sequencing showed an increased DNA methylation of many genes and bisulfite sequencing analysis showed an increased DNA methylation of Smad7 after alcohol ingestion. We also found DNA methylation of Smad7 was mediated by DNMT1 in ethyl alcohol (EtOH)-treated HK2 cells. Knockdown of Nox2 or Nox4 decreased DNMT1 and rebalanced Smad7/Smad3 axis, and thereby relieved EtOH-induced fibrotic response. The inhibition of reactive oxygen species by the intraperitoneal injection of apocynin attenuated renal fibrosis and restored renal function in the alcoholic mice. Collectively, we established novel in vivo and in vitro alcoholic kidney fibrosis models and found that alcohol induces renal fibrosis by activating oxidative stress-induced DNA methylation of Smad7. Suppression of Nox-mediated oxidative stress may be a potential therapy for long-term alcohol abuse-induced kidney fibrosis.


Assuntos
Metilação de DNA/genética , Etanol/efeitos adversos , Nefropatias/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Proteína Smad7/metabolismo , Acetofenonas/farmacologia , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Túbulos Renais/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
20.
Am J Physiol Renal Physiol ; 318(3): F660-F672, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31984793

RESUMO

Gα12 and Gα13 are ubiquitous members of the heterotrimeric guanine nucleotide-binding protein (G protein) family that play central and integrative roles in the regulation of signal transduction cascades within various cell types in the kidney. Gα12/Gα13 proteins enable the kidney to adapt to an ever-changing environment by transducing stimuli from cell surface receptors and accessory proteins to effector systems. Therefore, perturbations in Gα12/Gα13 levels or their activity can contribute to the pathogenesis of various renal diseases, including renal cancer. This review will highlight and discuss the complex and expanding roles of Gα12/Gα13 proteins on distinct renal pathologies, with emphasis on more recently reported findings. Deciphering how the different Gα12/Gα13 interaction networks participate in the onset and development of renal diseases may lead to the discovery of new therapeutic strategies.


Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Nefropatias/metabolismo , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Humanos , Nefropatias/genética
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