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1.
Am J Chin Med ; 48(6): 1455-1473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32933312

RESUMO

Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza, Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro. These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.


Assuntos
Abietanos/farmacologia , Abietanos/uso terapêutico , Cálculos Renais/tratamento farmacológico , Cálculos Renais/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Salvia miltiorrhiza/química , Ácido Úrico/metabolismo , Abietanos/isolamento & purificação , Animais , Células Cultivadas , Cristalização , Modelos Animais de Doenças , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cálculos Renais/etiologia , Camundongos , Camundongos Endogâmicos , Extratos Vegetais/isolamento & purificação
2.
Ann Biol Clin (Paris) ; 78(4): 349-362, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540796

RESUMO

The prevalence of crystalline pathologies including urolithiasis, gallstones, vascular calcifications and crystalline arthritis, is very high in the general population beyond 60 years old. Characterization of microcrystals in tissue at the micrometer and at the nanometer scale through physico-chemical techniques constitutes a new opportunity for the physician to decipher the early stage of the pathogenesis of these biological entities. In this review, such description indicates a wide variety of the chemical process associated to the nucleation process directly from supersaturated solution or from organic support such as DNA or elastin. We will also discuss the case of vesicles which play a major role in the case of ectopic calcification situated in kidney tissue, namely the Randall's plaque. All this research focused on the very first steps of the genesis of pathological calcifications constitute a major step to develop specific therapy able to avoid the formation of these abnormal deposits in tissues. As already underlined, crystals may be the consequence of various pathologies, but they are also involved in the dysfunction of the tissues.


Assuntos
Calcinose/etiologia , Cristalização , Litíase/etiologia , Calcinose/metabolismo , Calcinose/patologia , Humanos , Cálculos Renais/etiologia , Cálculos Renais/metabolismo , Cálculos Renais/patologia , Litíase/metabolismo , Litíase/patologia , Urolitíase/etiologia , Urolitíase/metabolismo , Urolitíase/patologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
3.
Curr Opin Pediatr ; 32(2): 284-287, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32068596

RESUMO

PURPOSE OF REVIEW: As the incidence of urinary stone disease in children is increasing, identifying dietary risk factors becomes vitally important, especially in the context of targeting interventions to reduce risk for stone formation. Indiscriminant dietary restrictions are not appropriate for paediatric patients. RECENT FINDINGS: Although large, prospective studies are still needed to better quantify dietary risk factors for paediatric stone formers, a number of smaller studies provide data to identify common risk factors to help prevent stone formation, while minimizing inappropriate dietary restrictions. SUMMARY: Interpretation of 24-h urine samples to identify individualized dietary risk factors is crucial for implementing a strategy for prevention of further urinary stone formation in children. Clinicians should avoid generalized dietary restrictions in stone-forming children uninformed by laboratory data.


Assuntos
Dieta/efeitos adversos , Cálculos Renais/etiologia , Doenças Metabólicas/diagnóstico , Cálculos Urinários/etiologia , Criança , Humanos , Cálculos Renais/metabolismo , Cálculos Renais/urina , Doenças Metabólicas/complicações , Doenças Metabólicas/urina , Fatores de Risco , Fatores Socioeconômicos , Cálculos Urinários/metabolismo , Cálculos Urinários/urina
4.
Int J Mol Med ; 45(2): 375-384, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894301

RESUMO

MicroRNAs (miRNAs or miRs) are critical regulators in various diseases. In the current study, the role of miR­30c­5p in the formation of sodium oxalate­induced kidney stones was investigated. For this purpose, human renal tubular epithelial cells (HK­2 cells) were incubated with sodium oxalate at the concentrations of 100, 250, 500, 750 and 1,000 µM. Cell viability and the miR­30c­5p expression level were respectively measured by CCK­8 assay and RT­qPCR. After separately transfecting miR­30c­5p mimic and inhibitor into the HK­2 cells, the cell apoptotic rate, the levels of mitochondrial membrane potential (MMP) and ROS were determined by flow cytometry. The levels of oxidative stress indicators [lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT)] were determined using commercial kits. Crystal­cell adhesion assay was performed to evaluate the crystal adhesion capacity in vitro. miR­30c­5p binding at autophagy related 5 (ATG5) was predicted by TargetScan7.2 and further verified by dual­luciferase reporter assay. Rescue experiments were performed to confirm the molecular mechanisms underlying sodium oxalate­induced kidney formation in HK­2 cells. The results revealed that sodium oxalate decreased the viability of HK­2 cells in a concentration­dependent manner, and that miR­30c­5p expression was significantly downregulated by exposure to 750 µM sodium oxalate. In addition, the increase in cell apoptosis and crystal number, and the upregulated levels of LDH, MDA and ROS were reversed by the overexpression of miR­30c­5p. Moreover, the overexpression of miR­30c­5p upregulated the levels of SOD, CAT and MMP induced by sodium oxalate. ATG5 was directly regulated by miR­30c­5p, and the inhibition of cell cytotoxicity and crystal­cell adhesion induced by miR­30c­5p mimic was blocked by ATG5. These data indicated that the overexpression of miR­30c­5p alleviated cell cytotoxicity and crystal­cell adhesion induced by sodium oxalate through ATG5. Thus, the current study provides a better understanding of the role of miR­30c­5p in sodium oxalate­induced kidney stones.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Cálculos Renais/genética , MicroRNAs/genética , Regulação para Cima , Apoptose , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Rim/metabolismo , Rim/patologia , Cálculos Renais/metabolismo , Cálculos Renais/patologia , Ácido Oxálico/metabolismo , Estresse Oxidativo
5.
Curr Opin Urol ; 30(2): 171-176, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31895888

RESUMO

PURPOSE OF REVIEW: The review of potential therapies in the treatment of hyperoxaluria is timely, given the current excitement with clinical trials and the mounting evidence of the importance of oxalate in both kidney stone and chronic kidney disease. RECENT FINDINGS: Given the significant contribution of both endogenous and dietary oxalate to urinary oxalate excretions, it is not surprising therapeutic targets are being studied in both pathways. This article covers the existing data on endogenous and dietary oxalate and the current targets in these pathways. SUMMARY: In the near future, there will likely be therapies targeting both endogenous and dietary oxalate, especially in subsets of kidney stone formers.


Assuntos
Hiperoxalúria/metabolismo , Hiperoxalúria/terapia , Oxalatos/efeitos adversos , Oxalatos/metabolismo , Adulto , Animais , Dieta/efeitos adversos , Humanos , Hiperoxalúria/etiologia , Cálculos Renais/química , Cálculos Renais/etiologia , Cálculos Renais/metabolismo , Cálculos Renais/terapia , Camundongos , Ratos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia
6.
Urolithiasis ; 48(1): 27-35, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30949730

RESUMO

Kidney stone is a chronic metabolic disease that caused by many factors, especially by the metabolic disturbances of urine compositions, but the metabolic profiling of the urine from kidney stone patients remains poorly explored. In the present study, 1H NMR spectroscopy and multivariate pattern recognition analytical techniques were combined to explore the metabolic profiling of the urine from kidney stone patients. A total of 216 urine samples obtained from kidney stone patients (n = 110) and healthy controls (n = 106) were investigated. The results indicated that principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) models were capable of distinguishing kidney stone patients from healthy controls. In addition, a total of 15 metabolites was obviously different in concentration between the two groups. Furthermore, four metabolic pathways, including glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, phenylalanine metabolism and citrate cycle (TCA cycle), were closely associated with kidney stone. Together, our results established a preliminary metabolic profiling of the urine from kidney stone patients via using 1H NMR-based analytical techniques for the first time and provided a novel method for recognizing and observing the kidney stone disease.


Assuntos
Cálculos Renais/diagnóstico , Espectroscopia de Prótons por Ressonância Magnética , Urina/química , Adulto , Idoso , Biomarcadores/metabolismo , Biomarcadores/urina , Estudos de Casos e Controles , Estudos de Viabilidade , Feminino , Voluntários Saudáveis , Humanos , Cálculos Renais/metabolismo , Cálculos Renais/urina , Masculino , Redes e Vias Metabólicas , Metabolômica/métodos , Pessoa de Meia-Idade , Adulto Jovem
8.
Am J Physiol Cell Physiol ; 318(2): C372-C379, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31825656

RESUMO

Most kidney stones are composed of calcium oxalate, and small increases in urine oxalate enhance the stone risk. The mammalian intestine plays a crucial role in oxalate homeostasis, and we had recently reported that Oxalobacter-derived factors stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells through PKA activation. We therefore evaluated whether intestinal oxalate transport is directly regulated by activation of the PKA signaling pathway. To this end, PKA was activated with forskolin and IBMX (F/I). F/I significantly stimulated (3.7-fold) [14C]oxalate transport by C2 cells [≥49% of which is mediated by the oxalate transporter SLC26A6 (A6)], an effect completely blocked by the PKA inhibitor H89, indicating that it is PKA dependent. PKA stimulation of intestinal oxalate transport is not cell line specific, since F/I similarly stimulated oxalate transport by the human intestinal T84 cells. F/I significantly increased (2.5-fold) A6 surface protein expression by use of immunocytochemistry. Assessing [14C]oxalate transport as a function of increasing [14C]oxalate concentration in the flux medium showed that the observed stimulation is due to a F/I-induced increase (1.8-fold) in Vmax and reduction (2-fold) in Km. siRNA knockdown studies showed that significant components of the observed stimulation are mediated by A6 and SLC26A2 (A2). Besides enhancing A6 surface protein expression, it is also possible that the observed stimulation is due to PKA-induced enhanced A6 and/or A2 transport activity in view of the reduced Km. We conclude that PKA activation positively regulates oxalate transport by intestinal epithelial cells and that PKA agonists might therapeutically impact hyperoxalemia, hyperoxaluria, and related kidney stones.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Mucosa Intestinal/metabolismo , Oxalatos/metabolismo , Transdução de Sinais/fisiologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Hiperoxalúria/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Transporte de Íons/fisiologia , Cálculos Renais/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Biomed Pharmacother ; 121: 109649, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733571

RESUMO

BACKGROUND: Nephrolithiasis is a common disease in urology, and its pathogenesis is associated with various factors. Recent studies have shown that reactive oxygen species (ROS) can promote autophagy in the formation of kidney stones and exacerbate kidney injury. Endoplasmic reticulum stress (ERS), a key factor in regulating intracellular environmental homeostasis, is also directly related to ROS production. Therefore, this study aimed to investigate the regulatory effect of superoxide dismutase (SOD) on autophagy-ERS response during the formation of calcium oxalate (CaOx) kidney stones in rats. METHODS: Thirty-two rats were randomly divided into four groups (n = 8): normal control group, stone model group, stone model with atorvastatin group, and stone model with diethyldithiocarbamic acid (DETC) group. Rat models of CaOx kidney stones were established by intragastric administration of 0.75 % ethylene glycol for 4 weeks. Kidney/body weight was used to assess renal enlargement. Renal function was assessed by measuring serum SOD, creatinine (CRE), and blood urea nitrogen (BUN) levels. The expression of autophagy-related proteins LC3B and BECN1 was detected through immunohistochemical staining. Meanwhile, the expression of autophagy-ERS response-related proteins LC3B, BECN1, p62, GRP78, and CHOP was detected using Western blot and RT-PCR. Renal tubular injury markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (Kim-1) were determined through enzyme-linked immunosorbent assay. The apoptosis of renal tubular cells and the expression of their signature proteins cleaved Caspase-3, Bax and Bcl-2 were detected using Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot assays, respectively. Crystal deposition and histological tissue injury were assessed through Von Kossa staining. RESULTS: Compared with the control group, the stone model group showed higher kidney/body weight ratio; evidently higher expression of autophagy-ERS response- and apoptosis-related proteins LC3B, BECN1, GRP78, CHOP, Bax and cleaved Caspase-3; and lower levels of p62, bcl-2 protein, and SOD. The stone model group also showed higher levels of apoptosis, serum CRE, BUN, NGAL, and Kim-1, as well as considerably greater crystal deposition and renal injury, than the control group. Atorvastatin reduced the levels of autophagy-ERS response, kidney injury, and crystal deposition, but they were increased by DETC. CONCLUSION: Enhanced SOD activity can protect the kidneys by reducing autophagy-ERS response and CaOx kidney stone formation. Atorvastatin may be a new option for the prevention and treatment of nephrolithiasis.


Assuntos
Autofagia/fisiologia , Oxalato de Cálcio/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Cálculos Renais/metabolismo , Cálculos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Superóxido Dismutase/metabolismo , Animais , Apoptose/fisiologia , Proteína 5 Relacionada à Autofagia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/metabolismo , Túbulos Renais/metabolismo , Masculino , Nefrolitíase/metabolismo , Nefrolitíase/fisiopatologia , Ratos , Ratos Sprague-Dawley
10.
Int J Mol Sci ; 20(24)2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861118

RESUMO

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall's plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.


Assuntos
Difosfatos/metabolismo , Cálculos Renais/metabolismo , Pseudoxantoma Elástico/metabolismo , Doenças Raras/metabolismo , Urolitíase/metabolismo , Calcificação Vascular/metabolismo , 5'-Nucleotidase/genética , Proteínas Ligadas por GPI/genética , Humanos , Cálculos Renais/complicações , Cálculos Renais/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/genética , Doenças Raras/complicações , Doenças Raras/genética , Urolitíase/complicações , Urolitíase/genética , Calcificação Vascular/complicações , Calcificação Vascular/genética
11.
Nat Commun ; 10(1): 5175, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729369

RESUMO

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45-60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.


Assuntos
Cálcio/metabolismo , Cálculos Renais/genética , Vitamina D/metabolismo , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão , Cálculos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas/genética , Proteínas/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Reino Unido
12.
Cells ; 8(9)2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547429

RESUMO

Nephrolithiasis/urolithiasis (i.e., kidney stone disease) remains a global public health problem with increasing incidence/prevalence. The most common chemical composition of kidney stones is calcium oxalate that initiates stone formation by crystallization, crystal growth, crystal aggregation, crystal-cell adhesion, and crystal invasion through extracellular matrix in renal interstitium. Among these processes, crystal-cell interactions (defined as "the phenomena in which the cell is altered by any means of effects from the crystal that adheres onto cellular surface or is internalized into the cell, accompanying with changes of the crystal, e.g., growth, adhesive capability, degradation, etc., induced by the cell") are very important for crystal retention in the kidney. During the past 12 years, proteomics has been extensively applied to kidney stone research aiming for better understanding of the pathogenic mechanisms of kidney stone formation. This article provides an overview of the current knowledge in this field and summarizes the data obtained from all the studies that applied proteomics to the investigations of crystal-cell interactions that subsequently led to functional studies to address the significant impact or functional roles of the expression proteomics data in the pathogenesis of kidney stone disease.


Assuntos
Oxalato de Cálcio/metabolismo , Adesão Celular/fisiologia , Cálculos Renais/metabolismo , Rim/metabolismo , Proteômica/métodos , Cristalização , Humanos , Rim/patologia , Cálculos Renais/patologia
13.
Am J Physiol Renal Physiol ; 317(5): F1342-F1349, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509008

RESUMO

Bacterial infection has long been recognized to contribute to struvite urinary stone deposition; however, its contribution to the development of chronic kidney stones has not been extensively investigated. In the present study, we hypothesized another possible method of bacteria contributing to the formation of calcium oxalate (CaOx) that accounts for the biggest part of the kidney stone. Bacteria may play important roles by influencing renal Ca2+-related ion channel activities, resulting in chronic inflammation of the kidney along with rapid aggregation of stones. We examined the correlation among infection-promoted CaOx kidney stones and alterations in Ca2+-related ion channels in an animal model with experimentally induced Proteus mirabilis and foreign body infection. After the bladder was infected for 7 days, the data demonstrated that stones were presented and induced severe renal tubular breakage as well as altered levels of monocyte chemoattractant protein-1, cyclooxygenase-2, osteopontin, and transient receptor potential vanilloid member 5 expression, reflecting responses of kidney ion channels. Monocyte chemoattractant protein-1, osteopontin, and transient receptor potential vanilloid member 5 expression was significantly downregulated over time, indicating the chronic inflammation phase of the kidney and accelerated aggregation of CaOx crystals, respectively, whereas cyclooxygenase-2 exhibited no differences. These results indicated that bacterial infection is considerably correlated with an alteration in renal Ca2+-related ion channels and might support specific and targeted Ca2+-related ion channel-based therapeutics for urolithiasis and related inflammatory renal damage.


Assuntos
Canais de Cálcio/metabolismo , Cálculos Renais/metabolismo , Urolitíase/metabolismo , Animais , Regulação da Expressão Gênica , Imunidade Inata , Rim/patologia , Infecções por Proteus/complicações , Proteus mirabilis , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Estruvita , Bexiga Urinária/patologia , Urolitíase/etiologia
14.
Proteomics ; 19(19): e1900095, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31475403

RESUMO

Females have less incidence/prevalence of kidney stone disease than males. Estrogen thus may serve as the protective factor but with unclear mechanism. This study explores cellular mechanism underlying such stone preventive mechanism of estrogen. Madin darby canine kidney (MDCK) renal tubular cells are incubated with or without 20 nm 17ß-estradiol for 7 days. Comparative proteomics reveals 58 differentially expressed proteins in estrogen-treated versus control cells that are successfully identified by nanoLC-ESI-Q-TOF-MS/MS. Interestingly, these altered proteins are involved mainly in "binding and receptor," "metabolic process," and "migration and healing" networks. Functional investigations demonstrate reduction of calcium oxalate (CaOx) crystal-binding capability of the estrogen-treated cells consistent with the decreased levels of annexin A1 and α-enolase (the known CaOx crystal-binding receptors) on the cell surface. High-calcium and high-oxalate challenge initially enhances surface expression of annexin A1 and α-enolase, respectively, both of which return to their basal levels by estrogen. Additionally, estrogen reduces intracellular ATP level and promotes cell migration and tissue healing. Taken together, estrogen causes changes in cellular proteome of renal tubular cells that lead to decreased surface expression of CaOx crystal receptors, reduced intracellular metabolism, and enhanced cell proliferation and tissue healing, all of which may contribute, at least in part, to stone prevention.


Assuntos
Estradiol/farmacologia , Cálculos Renais/prevenção & controle , Proteoma/metabolismo , Proteômica/métodos , Animais , Oxalato de Cálcio/química , Oxalato de Cálcio/metabolismo , Células Cultivadas , Cromatografia Líquida/métodos , Cristalização , Cães , Estrogênios/farmacologia , Cálculos Renais/metabolismo , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Nanotecnologia/métodos , Substâncias Protetoras/farmacologia , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
15.
Prog Urol ; 29(16): 962-973, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31537493

RESUMO

INTRODUCTION: Genetic factors must be considered in etiological diagnosis of urinary lithiasis. The aim of this study was to determine clinical, metabolic characteristics and the progression of hereditary urinary lithiasis in our patients. METHODS: A retrospective study was conducted between 2008 and 2018 and 60 patients were included. Patients were referred to our department from pediatrics departments to be followed-up in adulthood in 9 cases, for etiological investigation in 42 cases and for chronic renal failure in 9 cases. RESULTS: Thirty-five men and twenty-five women were enrolled in this study with a M/F sex ratio equal to 1.4. The mean age at the time of diagnosis of the hereditary character of the urinary lithiasis was 28.6years (3months-63years). The average delay between the onset of the lithiasis disease and the etiological diagnosis was 8years (0-42years). We noted 31 cases of cystinuria, 18 cases of primary hyperoxaluria type 1 with two mutations (I244T in 14 cases, 33-34 Insc in 23 cases) and 11 cases of renal tubulopathy. Fourteen patients were affected with chronic renal failure, of which five were in the end-stage renal disease. Crystalluria was positive in 62% of cases. The morpho-constitutional analysis of stones was performed in 37 cases and it contributed to the diagnosis in 29 cases. After an average follow-up of 16years, we noted normal renal function in 42 cases, chronic renal failure in 7 cases, hemodialysis in 10 cases all with primary hyperoxaluria and transplantation in 1 case. CONCLUSION: The etiological diagnosis of hereditary urinary lithiasis in our study was made with considerable delay. Cystinuria was the most frequent etiology and primary hyperoxaluria was the most serious affection. LEVEL OF EVIDENCE: 4.


Assuntos
Cálculos Renais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Hospitais Especializados , Humanos , Lactente , Cálculos Renais/complicações , Cálculos Renais/diagnóstico , Cálculos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrologia , Estudos Retrospectivos , Adulto Jovem
16.
PLoS Genet ; 15(8): e1008318, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31415568

RESUMO

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.


Assuntos
Gota/etiologia , Cálculos Renais/etiologia , Redes e Vias Metabólicas/genética , Transdução de Sinais/genética , Ácido Úrico/metabolismo , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Modelos Animais de Doenças , Drosophila melanogaster , Comportamento Alimentar , Feminino , Técnicas de Silenciamento de Genes , Gota/metabolismo , Humanos , Insulina/metabolismo , Cálculos Renais/metabolismo , Longevidade/genética , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Polimorfismo de Nucleotídeo Único , Purinas/administração & dosagem , Purinas/efeitos adversos , Urato Oxidase/genética , Urato Oxidase/metabolismo
17.
Am J Pathol ; 189(11): 2171-2180, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31449775

RESUMO

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6-/- mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6-/- and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2 g/L in drinking water), both vitamin D supplementation and a calcium-rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3-dimensional microcomputed tomography, µ-Fourier transform infrared spectroscopy, field emission-scanning electron microscopy, transmission electron microscopy, and Yasue staining. At 6 months, Abcc6-/- mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared with control Abcc6-/- mice (P < 0.01). Wild-type animals did not develop significant calcifications when exposed to vitamin D. Combined administration of vitamin D and calcium significantly accelerates Randall's plaque formation in a murine model. This original model raises concerns about the cumulative risk of vitamin D supplementation and calcium intakes in Randall's plaque formation.


Assuntos
Cálcio na Dieta/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Cálculos Renais/induzido quimicamente , Medula Renal/metabolismo , Vitamina D/efeitos adversos , Animais , Calcinose/induzido quimicamente , Calcinose/metabolismo , Calcinose/patologia , Cálcio na Dieta/administração & dosagem , Modelos Animais de Doenças , Progressão da Doença , Feminino , Cálculos Renais/metabolismo , Cálculos Renais/patologia , Medula Renal/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Fatores de Tempo , Vitamina D/administração & dosagem
18.
Am J Physiol Renal Physiol ; 317(6): F1475-F1482, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461349

RESUMO

Randall's plaque (RP; subepithelial calcification) appears to be an important precursor of kidney stone disease. However, RP cannot be noninvasively detected. The present study investigated candidate biomarkers associated with extracellular vesicles (EVs) in the urine of calcium stone formers (CSFs) with low (<5% papillary surface area) and high (≥5% papillary surface area) percentages of RP and a group of nonstone formers. RPs were quantitated via videotaping and image processing in consecutive CSFs undergoing percutaneous surgery for stone removal. Urinary EVs derived from cells of different nephron segments of CSFs (n = 64) and nonstone formers (n = 40) were quantified in biobanked cell-free urine by standardized and validated digital flow cytometer using fluorophore-conjugated antibodies. Overall, the number of EVs carrying surface monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL) were significantly lower in CSFs compared with nonstone former controls (P < 0.05) but did not differ statistically between CSFs with low and high RPs. The number of EVs associated with osteopontin did not differ between any groups. Thus, EVs carrying MCP-1 and NGAL may directly or indirectly contribute to stone pathogenesis as evidenced by the lower of these populations of EVs in stone formers compared with nonstone formers. Validation of EV-associated MCP-1 and NGAL as noninvasive biomarkers of kidney stone pathogenesis in larger populations is warranted.


Assuntos
Oxalato de Cálcio , Cálculos Renais/metabolismo , Lipocalina-2/urina , Néfrons/metabolismo , Adulto , Biomarcadores/urina , Quimiocina CCL2/urina , Espaço Extracelular/metabolismo , Feminino , Humanos , Masculino , Osteopontina/urina
20.
Oxid Med Cell Longev ; 2019: 5305014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178964

RESUMO

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERß) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERß could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERß suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5' promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERß (ERßKO) as well as mice or rats treated with ERß antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERß-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERß may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.


Assuntos
Oxalato de Cálcio/metabolismo , Receptor beta de Estrogênio/metabolismo , Cálculos Renais/metabolismo , Rim/metabolismo , Fígado/metabolismo , Estresse Oxidativo/fisiologia , Animais , Feminino , Células HEK293 , Células Hep G2 , Humanos , Rim/patologia , Cálculos Renais/patologia , Cálculos Renais/prevenção & controle , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout
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