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1.
Life Sci ; 259: 118379, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32890604

RESUMO

With the increasing application of medical imaging contrast materials, contrast-induced nephropathy has become one of the leading causes of iatrogenic renal insufficiency. The underlying mechanism is associated with renal medullary hypoxia, direct toxicity of contrast agents, oxidative stress, apoptosis, immune/inflammation and epigenetic regulation in contrast-induced nephropathy. Up to date, there is no effective therapy for contrast-induced nephropathy, and thus risk predication and effective preventive strategies are keys to reduce the occurrence of contrast-induced nephropathy. It was found that the proper use of contrast medium, personalized hydration, and high-dose statins may reduce the occurrence of contrast-induced nephropathy, while antioxidants have not shown significant therapeutic benefits. Additionally, the role of remote ischemia preconditioning and vasodilators in the prevention of contrast-induced nephropathy needs further study. This review aims to discuss the incidence, pathogenesis, risk prediction, and preventive strategies for contrast-induced nephropathy.


Assuntos
Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Humanos , Rim/efeitos dos fármacos , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos
2.
Rev Med Suisse ; 16(703): 1483-1488, 2020 Aug 26.
Artigo em Francês | MEDLINE | ID: mdl-32852168

RESUMO

The landmark study EMPA-REG OUTCOME firstly demonstrated both a cardiovascular and renal protection with empagliflozin in patients with type 2 diabetes (T2DM) and established cardiovascular disease. Since 2015, two other trials showed a reduction in the hospitalisations for heart failure and the progression of the renal disease, also in patients with multiple risk factors, CANVAS with canagliflozin and DECLARE-TIMI 58 with dapagliflozin. CREDENCE (canagliflozin in T2DM patients with kidney disease) confirmed a renal protection and DAPA-HF (dapagliflozin in patients, with or without T2DM, but reduced ejection fraction) showed a less acute deterioration of heart failure. The positive effect of SGLT2 inhibitors on heart failure predominates, an effect recently confirmed in VERTIS CV with ertugliflozin.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias , Inibidores do Transportador 2 de Sódio-Glicose , Canagliflozina , Doenças Cardiovasculares/induzido quimicamente , Humanos , Hipoglicemiantes , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
3.
Oncology ; 98(9): 612-620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32485713

RESUMO

INTRODUCTION: Conventional first-line chemotherapy for patients with metastatic urothelial carcinoma (UC) is gemcitabine and cisplatin (GC). However, cisplatin can cause renal failure, necessitating abundant fluid replacement and hospitalization during treatment. Recent evidence exists for short hydration methods in cisplatin-based chemotherapy. OBJECTIVE: This study aims to analyze the efficacy of newly established modified short hydration GC (m-shGC) therapy in patients with UC. METHODS: From May 2017 to March 2019, 48 patients with UC who received m-shGC therapy were treated with 1,000 mg/m2 gemcitabine on days 1, 8, and 15, and 70 mg/m2 cisplatin and 2,000 mL fluid replacement on day 1, in each 28-day cycle. We retrospectively evaluated renal function, serum electrolyte abnormalities, and adverse events (AEs) following treatment, and retrospectively compared patients under m-shGC therapy with those under conventional GC (c-GC) therapy from 2015 to 2017. In addition, from April 2019 to August 2019 in a prospective analysis, 15 patients were newly enrolled, and AE profiles and physical activity during m-shGC therapy were quantified using a wearable tracker. RESULTS: In a retrospective analysis of 101 patients (53 c-GC and 48 m-shGC), patient characteristics were not statistically significant between the two groups. Myelosuppression, including predominant neutropenia and decreased platelets, fatigue, nausea, and constipation were the main common AEs. However, renal function and serum sodium levels in the m-shGC group remained unchanged. Grade 3-4 AEs were not more severe in the m-shGC compared with the c-GC group. Furthermore, in a prospective analysis using a wearable tracker, the amount of walking by patients on day 1 significantly declined. However, immediate recovery occurred reflecting the short hydration. CONCLUSION: Our m-shGC therapy has an acceptable AE profile compared with conventional therapy, with UC patients showing good physical activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidratação/métodos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Creatinina/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Hiponatremia/sangue , Hiponatremia/induzido quimicamente , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sódio/sangue , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias Urológicas/sangue
4.
Am J Physiol Renal Physiol ; 318(6): F1489-F1499, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390513

RESUMO

Recently, we reported that obese Dahl salt-sensitive (SS) leptin receptor mutant (SSLepRmutant) rats display progressive renal injury. The present study demonstrated that the early development of renal injury in the SSLepRmutant strain is associated with an increase in the renal infiltration of macrophages compared with lean SS rats. We also examined whether depletion of macrophages with clodronate would reduce the early progression of renal injury in the SSLepRmutant strain. Four-week-old SS and SSLepRmutant rats were treated with either vehicle (PBS) or clodronate (50 mg/kg ip, 2 times/wk) for 4 wk. While the administration of clodronate did not reduce renal macrophage infiltration in SS rats, clodronate decreased macrophages in the kidneys of SSLepRmutant rats by >50%. Interestingly, clodronate significantly reduced plasma glucose, insulin, and triglyceride levels and markedly improved glucose tolerance in SSLepRmutant rats. Treatment with clodronate had no effect on the progression of proteinuria or renal histopathology in SS rats. In the SSLepRmutant strain, proteinuria was markedly reduced during the first 2 wk of treatment (159 ± 32 vs. 303 ± 52 mg/day, respectively). However, after 4 wk of treatment, the effect of clodronate was no longer observed in the SSLepRmutant strain (346 ± 195 vs. 399 ± 50 mg/day, respectively). The kidneys from SSLepRmutant rats displayed glomerular injury with increased mesangial expansion and renal fibrosis versus SS rats. Treatment with clodronate significantly decreased glomerular injury and renal fibrosis in the SSLepRmutant strain. Overall, these data indicate that the depletion of macrophages improves metabolic disease and slows the early progression of renal injury in SSLepRmutant rats.


Assuntos
Ácido Clodrônico/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores para Leptina/genética , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose , Insulina/sangue , Rim/metabolismo , Rim/patologia , Nefropatias/sangue , Nefropatias/etiologia , Nefropatias/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Mutação , Obesidade/sangue , Obesidade/complicações , Obesidade/genética , Ratos Endogâmicos Dahl , Fatores Sexuais , Fatores de Tempo , Triglicerídeos/sangue
5.
Life Sci ; 253: 117729, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348836

RESUMO

Obstructive nephropathy is a common clinical case that causes chronic kidney disease and ultimately progresses to end-stage renal disease. The activation of peroxisome proliferator-activated receptor-α (PPAR-α) reduces tubulointerstitial fibrosis and inflammation associated with obstructive nephropathy. AIMS: This study was carried out to investigate the potential effect of saroglitazar, dual PPAR-α/γ agonist, in alleviating renal fibrosis induced by unilateralureteral obstruction (UUO). MAIN METHODS: Twenty-four male Sprague Dawley rats were haphazardly divided into four groups of six rats each, including sham operated group, vehicle- or saroglitazar-treated UUO and saroglitazar groups. Rats received oral gavage of saroglitazar (3 mg/kg/day) for 13 days. On day 14, all rats were sacrificed; blood and renal tissues were collected. KEY FINDINGS: Saroglitazar inhibited UUO-induced oxidative stress; it decreased the elevated levels of MDA and nitric oxide and increased levels of GSH and SOD in renal tissue. Moreover, saroglitazar repressed UUO-induced inflammation; it decreased the renal levels of nuclear factor kappa B (NF-κB) and interleukin-6 (IL-6). Furthermore, saroglitazar inhibited the accumulation of extracellular matrix via decreasing collagen, hydroxylproline and matrix metalloproteinase-9 (MMP-9) levels. Saroglitazar also decreased the expression of both the alpha smooth muscle actin (α-SMA) and tumor growth factor-beta (TGF-ß). These effects were in parallel with reduction in mothers against decapentaplegic homolog 3 (smad3) expression and plasminogen activator inhibitor-1 (PAI-1) levels. SIGNIFICANCE: Collectively, the protective impact of saroglitazar might be attributed to its antioxidant, anti-inflammatory and anti-fibrotic effects against UUO-induced tubulointerstitial fibrosis through its regulatory effect on TGF-ß1/Smad3 signaling pathway.


Assuntos
Inflamação/prevenção & controle , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Fenilpropionatos/farmacologia , Pirróis/farmacologia , Obstrução Ureteral/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibrose , Inflamação/patologia , Nefropatias/fisiopatologia , Masculino , PPAR alfa/agonistas , PPAR gama/agonistas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/complicações
6.
Arch Biochem Biophys ; 687: 108387, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348741

RESUMO

Although acetaminophen (APAP) is a commonly used analgesic antipyretic drug, hepatotoxicity and nephrotoxicity are common after the overdose. The main mechanism of APAP toxicity is oxidative stress based. Stress may induce the production of heme oxygenase 1 (HO)-1 which is regulated by interleukin (IL)-10 and inhibit the production of tumor necrosis factor-alpha (TNF-α). HO-1 expression is further regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor BTB and CNC homology 1 (BACH1). Drug-induced toxicity can be relieved by several natural products, which are preferred due to their dietary nature and less adverse reactions. Of these natural products, omega-3 (ω-3) fatty acids are known for anti-inflammatory and antioxidant actions. However, effects of ω-3fatty acids on APAP-induced hepatic and renal toxicity are not well addressed. We designed this study to test the potential protecting actions of ω-3 fatty acids (270 mg/kg Eicosapentaenoic acid and 180 mg/kg docosahexaenoic acid, orally, for 7 days) in hepatotoxicity and nephrotoxicity induced by APAP (2 g/kg, once orally on day 7) in rats. Moreover, we focused on the molecular mechanism underlying APAP hepatotoxicity and nephrotoxicity. Pre-treatment with ω-3 fatty acids enhanced liver and kidney functions indicated by decreased serum aminotransferases activities and serum creatinine and urea concentrations. These results were further confirmed by histopathological examination. Moreover, ω-3 fatty acids showed antioxidant properties confirmed by decreased malondialdehyde level and increased total antioxidant capacity. Antioxidant Nrf2, its regulators (HO-1 and BACH1) and the anti-inflammatory cytokine (IL-10) were up-regulated by APAP administration as a compensatory mechanism and they were normalized by ω-3 fatty acids. ω-3 fatty acids showed anti-inflammatory actions through down-regulating nuclear factor kappa B (NF-ĸB) and its downstream TNF-α. Moreover, Western blot analysis showed that ω-3 fatty acids promoted Nrf2 translocation to the nucleus; BACH1 exit from the nucleus and inhibited NF-ĸB nuclear translocation. These findings suggested the protecting actions of ω-3 fatty acids against APAP-induced hepatic and renal toxicity through regulation of antioxidant Nrf2 and inflammatory NF-ĸB pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ácidos Graxos Ômega-3/farmacologia , Nefropatias/prevenção & controle , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetaminofen , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Núcleo Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação para Baixo , Heme Oxigenase (Desciclizante)/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Fígado/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Proteínas Repressoras/metabolismo , Fator de Crescimento Transformador alfa/metabolismo
7.
Rev Med Suisse ; 16(683): 412-416, 2020 Feb 26.
Artigo em Francês | MEDLINE | ID: mdl-32129019

RESUMO

Over the last decades, an increasing number of cases of chronic and end-stage kidney disease has been observed in Central America and Asia. This kidney disease mainly affects young farmers without classic renal risk factors. The clinical presentation includes a progressive decrease of the glomerular filtration rate, minimal proteinuria and the presence of tubulo-interstitial nephritis at renal biopsy. A close link with global warming is suspected for this disease, called (according to its location) meso-american nephropathy, Sri Lanka nephropathy or chronic kidney disease of unknown etiology. Others have suggested that intake of water contaminated with pesticides may be responsible. This article provides an overview of this new kidney disease. Measures to prevent acute kidney injury during heat waves in Switzerland are also discussed.


Assuntos
Aquecimento Global , Nefropatias/epidemiologia , Nefropatias/etiologia , Rim/patologia , Rim/fisiopatologia , América Central/epidemiologia , Humanos , Nefropatias/prevenção & controle , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Sri Lanka/epidemiologia , Suíça/epidemiologia
8.
Am J Physiol Renal Physiol ; 318(5): F1160-F1166, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174141

RESUMO

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-ß, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-ß, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson's trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.


Assuntos
Nefropatias/metabolismo , Rim/patologia , Proteínas de Membrana Transportadoras/deficiência , Obstrução Ureteral/complicações , Actinas/metabolismo , Animais , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibrose , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Vimentina/metabolismo
9.
Am J Physiol Renal Physiol ; 318(5): F1122-F1135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174138

RESUMO

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na+ and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). Apelin was also found in the medullary CDs as assessed by immunofluorescence. In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of full-length PRR (fPRR), soluble PRR (sPRR), and prorenin/renin protein expression as assessed by immunoblotting and medium sPRR and prorenin/renin levels by ELISA, all of which were reversed by 8-bromoadenosine 3',5'-cyclic monophosphate. Conversely, deletion of PRR in the CD or nephron in mice elevated Apela and Apln mRNA levels as well as urinary ELA and apelin excretion, supporting the antagonistic relationship between the two systems. Administration of exogenous ELA-32 infusion (1.5 mg·kg-1·day-1, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure, systolic blood pressure, diastolic blood pressure, and albuminuria, accompanied with a reduction of urinary sPRR, angiotensin II, and prorenin/renin excretion. HS upregulated renal medullary protein expression of fPRR, sPRR, prorenin, and renin in Dahl SS rats, all of which were significantly blunted by exogenous ELA-32 infusion. Additionally, HS-induced upregulation of inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-17A, IFN-γ, VCAM-1, ICAM-1, and MCP-1), fibrosis markers (TGF-ß1, FN, Col1A1, PAI-1, and TIMP-1), and kidney injury markers (NGAL, Kim-1, albuminuria, and urinary NGAL excretion) were markedly blocked by exogenous ELA infusion. Together, these results support the antagonistic interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.


Assuntos
Pressão Sanguínea , Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Hormônios Peptídicos/metabolismo , Sistema Renina-Angiotensina , Animais , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Nefropatias/prevenção & controle , Masculino , Camundongos Knockout , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/genética , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Ratos Endogâmicos Dahl , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais
10.
Am J Physiol Renal Physiol ; 318(4): F1041-F1052, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150448

RESUMO

Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na+-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.


Assuntos
Apoptose/efeitos dos fármacos , Canagliflozina/farmacologia , Cisplatino , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Citocromos c/metabolismo , Citoproteção , Modelos Animais de Doenças , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Rim/enzimologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/enzimologia , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Am J Pathol ; 190(4): 799-816, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32220420

RESUMO

Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.


Assuntos
Nefropatias/prevenção & controle , Glomérulos Renais/citologia , Podócitos/citologia , Substâncias Protetoras/metabolismo , Receptores Imunológicos/deficiência , Adulto , Animais , Feminino , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Ratos
12.
Artigo em Inglês | MEDLINE | ID: mdl-32186196

RESUMO

Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules, quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using a specific PARP inhibitor PJ 34 hydrochloride (PJ34) or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish are not only suitable for drug screening and genetic manipulation but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.


Assuntos
Cisplatino , Nefropatias/enzimologia , Túbulos Renais/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Benzamidas/farmacologia , Dano ao DNA , Modelos Animais de Doenças , Nefropatias/induzido quimicamente , Nefropatias/patologia , Nefropatias/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Fenantrenos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transdução de Sinais , Peixe-Zebra
13.
Expert Rev Cardiovasc Ther ; 18(1): 33-39, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32003265

RESUMO

Introduction: Contrast-induced nephropathy is a known complication that can occur after intravascular administration of iodinated contrast medium. Its consequences can range from a mild worsening of the renal function to renal failure requiring renal replacement therapy. There is no known effective treatment for contrast-induced nephropathy, and thus, efforts have focused on its prevention. Many approaches have been studied, but the most common strategy in use at the present time is prophylactic intravenous isotonic saline.Areas covered: This article reviews the data supporting the current practice of prophylactic periprocedural intravenous isotonic saline for lowering the incidence of contrast-induced nephropathy. We reviewed PubMed to search primarily for the latest clinical trials and meta-analyses pertaining to contrast-induced nephropathy and the use of prophylactic measures, specifically intravenous infusion of isotonic saline.Expert commentary: Currently, there are no universally accepted methods for the prevention of contrast-induced nephropathy. The best evidence for contrast-induced nephropathy prophylaxis is the administration of intravenous isotonic saline. Our review article provides an overview of the current knowledge, latest research, and current practice on contrast-induced nephropathy prophylaxis using intravenous isotonic saline administration.


Assuntos
Cateterismo Cardíaco/métodos , Angiografia Coronária/métodos , Nefropatias/prevenção & controle , Cateterismo Cardíaco/efeitos adversos , Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Humanos , Infusões Intravenosas , Nefropatias/induzido quimicamente , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/prevenção & controle , Resultado do Tratamento
14.
Acta Cir Bras ; 34(12): e201901201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32022101

RESUMO

PURPOSE: To evaluate the effect of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor, able to modulate the histological changes caused by the NASID (meloxicam). METHODS: Wistar rats were assigned into three groups (n=6 rats/group): Sham group (saline solution), NSAID group (meloxicam - 15 mg/kg) and Rut-bpy group (100 mg/kg of Rut-bpy associated with 15mg/kg of meloxicam). At the end of experiments, kidneys were removed for histological study, fractal dimension and lacunarity in all animals. RESULTS: At the histological examination, all animals (six animals - 100 %) in the NSAID group had membrane thickening and other changes (necrosis, acute tubular congestion and vascular congestion); on the other hand, only one animal (16.6 %) of the Rut-bpy group had congestion. The fractal dimension and lacunarity were greater in the control and Rut-bpy group than in NSAIDs group (p<0.05). CONCLUSION: Rut-bpy may prevent renal histological changes in rats caused by meloxicam.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Meloxicam/efeitos adversos , Doadores de Óxido Nítrico/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , 2,2'-Dipiridil/análogos & derivados , Animais , Fractais , Nefropatias/patologia , Masculino , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes
15.
Chem Biol Interact ; 318: 108977, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32035863

RESUMO

Excess weight and obesity increase the risk of developing major risk factors for chronic kidney disease. Lignin comprises 20%-30% of the global plant biomass; however, it is not well utilized because of its resistance to chemical and biological degradation. We investigated whether low-molecular-weight oxidized lignophenol (LOLP), a lignin derivative, could alter inflammation and fibrosis in the kidneys of a high-fat diet (HFD)-fed mice. Male mice were divided into three treatment groups: HFD; HFD +0.3% LOLP; and HFD +0.6% LOLP. The control mice (Cont) were fed a low-fat diet. Macrophage kinetics, the degree of fibrosis, the extent of phosphorylation of AMP-activated protein kinase (AMPK), and mRNA expression of proinflammatory mediators in the kidneys were examined. The number of macrophages, the percentage of fibrotic area, and the mRNA expression of proinflammatory markers, TNF-α and Ccl2, and a marker of fibrosis, TGF-ß, were significantly higher in the kidneys of mice in the HFD group than those in the Cont group. Conversely, treatment with 0.6% LOLP for 8 weeks significantly suppressed the degree of macrophage infiltration, interstitial fibrotic area, and the increased mRNA expression of proinflammatory and fibrosis markers induced by HFD. In conclusion, LOLP suppressed macrophage infiltration and the increase in fibrotic area, and upregulated AMPK phosphorylation in the kidneys of HFD-fed mice; thus, it may ameliorate HFD-induced kidney injury.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Dieta Hiperlipídica/efeitos adversos , Nefropatias/induzido quimicamente , Lignina/química , Fenóis/química , Fenóis/farmacologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Ativação Enzimática/efeitos dos fármacos , Fibrose/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Nefropatias/prevenção & controle , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo
16.
Adv Pharmacol ; 87: 257-276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089235

RESUMO

Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known Chinese traditional medicine to improve health and to treat numerous diseases for over 2000 years in Asian countries. G. lucidum has the abundant chemical components such as triterpenes and polysaccharides, which have various biological activities including anti-oxidation, anti-inflammation, anti-liver disorders, anti-tumor growth and metastasis, etc. Recently, many lines of studies have elucidated the therapeutic effects of G. lucidum and its extractions on various acute kidney injury (AKI) and chronic kidney disease (CKD) pathogenesis, including autosomal dominant polycystic kidney disease, diabetic nephropathy, renal proximal tubular cell oxidative damage and fibrotic process, renal ischemia reperfusion injury, cisplatin-induced renal injury, adriamycin-induced nephropathy, chronic proteinuric renal diseases, etc. Clinical researches also showed potent anti-renal disease bioactivities of G. lucidum. In this chapter, we review experimental and clinical researches and provide comprehensive insights into the renoprotective effects of G. lucidum. In recent years, renal diseases have gradually aroused attention on account of their booming prevalence worldwide and lack of effective therapies. Although the complicated pathogenesis of kidney diseases, such as acute kidney injury (AKI) and chronic kidney diseases (CKD) have been intensively studied. The morbidity and mortality of AKI and CKD still rise continuously. Thanks to the conventional experience and the multi-target characteristics, natural products have been increasingly recognized as an alternative source for treating renal diseases.


Assuntos
Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Rim/lesões , Reishi/química , Produtos Biológicos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Rim/patologia , Nefropatias/induzido quimicamente , Polissacarídeos/uso terapêutico
17.
Expert Opin Drug Saf ; 19(2): 167-186, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31914328

RESUMO

Introduction: Aminoglycosides have been long used for antibacterial treatment and are still commonly used in clinical practice. Despite their extensive application and positive effects, drug-related toxicity is considered as the main obstacle for aminoglycosides. Aminoglycosides induce nephrotoxicity through the endocytosis and accumulation of the antibiotics in the epithelial cells of proximal tubule. Most importantly, however, a number of pharmacological agents were demonstrated to have protective activities against nephrotoxicity in experimental animals.Areas covered: In the present systematic review, the authors provide and discuss the mechanisms and epidemiological features of aminoglycoside-induced nephrotoxicity, and focus mainly on recent discoveries and key features of pharmacological interventions. In total, 39 articles were included in this review.Expert opinion: The majority of studies investigated gentamicin-induced nephrotoxicity in animal models. Antioxidants, chemicals, synthetic drugs, hormones, vitamins, and minerals showed potential values to prevent gentamicin-induced nephrotoxicity. Indicators used to evaluate the effectiveness of nephroprotection included antioxidative indexes, inflammatory responses, and apoptotic markers. Among the nephroprotective agents studied, herbs and natural antioxidant agents showed excellent potential to provide a protective strategy against gentamicin-induced nephrotoxicity.


Assuntos
Aminoglicosídeos/efeitos adversos , Antibacterianos/efeitos adversos , Nefropatias/prevenção & controle , Substâncias Protetoras/administração & dosagem , Aminoglicosídeos/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Gentamicinas/administração & dosagem , Gentamicinas/efeitos adversos , Humanos , Nefropatias/induzido quimicamente , Substâncias Protetoras/farmacologia
18.
Med J Aust ; 212(3): 133-139, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31910303

RESUMO

Treatment options for type 2 diabetes have expanded. While metformin remains the first line treatment in most cases, choices for second line treatment now extend beyond sulfonylureas and include the sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors. SGLT2 inhibitors are recommended for people with atherosclerotic cardiovascular disease, heart failure or kidney disease. Diabetic ketoacidosis is an uncommon but important side effect; its occurrence can be minimised with appropriate patient education and management, especially during perioperative periods and times of illness. GLP1 receptor agonists are recommended for people with atherosclerotic cardiovascular disease. Gastrointestinal side effects are common but are less prominent with the longer acting agents and can be minimised with slow titration of the shorter acting agents. DPP4 inhibitors are generally well tolerated, but alogliptin and saxagliptin should be used with caution in people with risk factors for heart failure. To optimise the management of type 2 diabetes, clinicians need to be aware of the pharmacological characteristics of each class of blood glucose-lowering medications and of the effect on cardiovascular health and renal function, balanced by potential adverse effects. Medications that have cardiovascular or renal benefits should be prescribed for patients with these comorbidities, and this is reflected in recent international guidelines.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Nefropatias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
19.
High Blood Press Cardiovasc Prev ; 27(1): 9-17, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31975151

RESUMO

The presence of hypertensive mediated organ damage is related to increased vascular risk and mortality and its prevention should be a therapeutic target and a surrogate marker of in/adequate blood pressure control. In old adult hypertensive patients the therapeutic target should be to prevent major cardiovascular events, but in young hypertensive subjects the focus should be pointed on preventing the development of hypertensive mediated organ damage, since most of the hard events are preceded by functional and structural tissues injury. Hypertension Guidelines of the European Society of Cardiology and European Society of Hypertension recognizes that some variables like electrocardiographic or echocardiographic left ventricle hypertrophy, chronic kidney disease or advance retinopathy, all considered as hypertensive mediated organ damage, may be modifiers of cardiovascular risk estimated by the SCORE system, and for that reason they should be screened in hypertensive patients. It is well known the problem of limited health systems financial resources in many low and even median income countries which precludes the possibilities of generalizing the search for hypertension mediated organ damage in all hypertensive patients. In these scenario the recommendation to perform a detailed screening should be critically evaluated. Some questions remained unanswered: the screening generalization of hypertensive mediated organ damage should modify the cardiovascular risk score of the patients, if its presence could modify the therapeutic approach, and as a consequence, if the treatment adjustment should prolong life expectancy and ameliorate the quality of life.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiopatias/prevenção & controle , Hipertensão/tratamento farmacológico , Nefropatias/prevenção & controle , Doenças Vasculares/prevenção & controle , Anti-Hipertensivos/efeitos adversos , Diagnóstico Precoce , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Cardiopatias/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/mortalidade , Nefropatias/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Doenças Vasculares/diagnóstico , Doenças Vasculares/mortalidade , Doenças Vasculares/fisiopatologia
20.
Rev Assoc Med Bras (1992) ; 66Suppl 1(Suppl 1): s17-s24, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939531

RESUMO

Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nefropatias/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Taxa de Filtração Glomerular , Glucose/metabolismo , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/metabolismo , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
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