RESUMO
We previously showed that SerpinA3K is present in urine from rats and humans with acute kidney injury (AKI) and chronic kidney disease (CKD). However, the specific role of SerpinA3K during renal pathophysiology is unknown. To begin to understand the role of SerpinA3K on AKI, SerpinA3K-deficient (KOSA3) mice were studied 24 h after inducing ischemia/reperfusion (I/R) and compared to wild type (WT) mice. Four groups were studied: WT+S, WT+IR, KOSA3+S, and KOSA3+IR. As expected, I/R increased serum creatinine and BUN, with a GFR reduction in both genotypes; however, renal dysfunction was ameliorated in the KOSA3+IR group. Interestingly, the increase in UH2O2 induced by I/R was not equally seen in the KOSA3+IR group, an effect that was associated with the preservation of antioxidant enzymes' mRNA levels. Additionally, FOXO3 expression was initially greater in the KOSA3 than in the WT group. Moreover, the increase in BAX protein level and the decrease in Hif1a and Vegfa induced by I/R were not observed in the KOSA3+IR group, suggesting that these animals have better cellular responses to hypoxic injury. Our findings suggest that SerpinA3K is involved in the renal oxidant response, HIF1α/VEGF pathway, and cell apoptosis.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Animais , Camundongos , Injúria Renal Aguda/metabolismo , Apoptose , Rim/metabolismo , Estresse Oxidativo , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. Ischemic preconditioning (IPC) has emerged as a promising strategy to prevent, to the extent possible, renal tissue from AKI. Several studies have used this strategy, which involves short or long cycles of ischemia/reperfusion (IR) prior to a potential fatal ischemic injury. In most of these studies, IPC was effective at reducing renal damage. Since the first study that showed renoprotection due to IPC, several studies have focused on finding the best strategy to activate correctly and efficiently reparative mechanisms, generating different modalities with promising results. In addition, the studies performing remote IPC, by inducing an ischemic process in distant tissues before a renal IR, are also addressed. Here, we review in detail existing studies on IPC strategies for AKI pathophysiology and the proposed triggering mechanisms that have a positive impact on renal function and structure in animal models of AKI and in humans, as well as the prospects and challenges for its clinical application.
Assuntos
Injúria Renal Aguda , Precondicionamento Isquêmico , Traumatismo por Reperfusão , Animais , Humanos , Traumatismo por Reperfusão/prevenção & controle , Rim/fisiologia , Precondicionamento Isquêmico/métodos , Isquemia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controleRESUMO
Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-ß, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Ratos , Animais , Heme Oxigenase-1 , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Insuficiência Renal Crônica/metabolismo , Rim/metabolismo , Isquemia/complicações , Anti-Inflamatórios/farmacologia , Heme/farmacologiaRESUMO
Fosfomycin (Fos) has emerged as a potential treatment against multidrug-resistant organisms, however, there has been little work done on its influence on calcineurin inhibitor nephrotoxicity (CIN). This study was designed to evaluate the effect of Fos in combination with cyclosporine (CsA) on CIN. Two sets of experiments were undertaken. In the first, Wistar rats received different doses of Fos: 0, 62.5, 125, 250, and 500 mg/kg. In the second, rats were divided into four groups: control, CsA 15 mg/kg s.c., CsA + fosfomycin 62.5 mg/kg (CsA + LF), and CsA + Fos 500 mg/kg (CsA + HF). CsA was administrated daily for 14 days, whereas Fos administration started on the ninth day followed by two more doses, delivered 48 h apart. The administration of different Fos doses did not alter renal function. In contrast, CsA induced arteriolopathy, hypoperfusion, a reduction in the glomerular filtration rate, and downregulation of eNOS, angiotensinogen, and AT1R mRNA levels. Lower doses of Fos did not modify CIN. Instead, the CsA + HF group exhibited greater hypoperfusion, arteriolopathy, and oxidative stress, and increased mRNA levels of pro-inflammatory cytokines. This study shows that Fos administered by itself at different doses did not cause renal injury, but when it was given repeatedly at high dosages (500 mg/kg) in combination with CsA, it increased CIN through the promotion of greater oxidative stress and renal inflammation.
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Resumen: OBJETIVO: Revisar la bibliografía más reciente para valorar y sintetizar los aspectos más importantes relacionados con las repercusiones del hipotiroidismo y su asociación con infertilidad en la mujer en edad reproductiva. METODOLOGÍA: Estudio de investigación documental consistente en la búsqueda en las bases electrónicas de PubMed y Google Scholar (1993-2018) con las palabras clave: hipotiroidismo subclínico, hipotiroidismo, disfunción tiroidea, hipofunción tiroidea, enfermedad de tiroides subclínica, pérdida de embarazo, aborto y embarazo; escritos en español e inglés y estudios retrospectivos publicados en libros de texto. RESULTADOS: Se incluyeron 39 documentos y se seleccionaron los de mayor relevancia científica y epidemiológica. El hipotiroidismo afecta a las mujeres en edad reproductiva con prevalencia de 0.4-0.5% para el evidente y 2-8% para el subclínico, este último puede resultar en infertilidad femenina y pobres desenlaces reproductivos. CONCLUSIÓN: El hipotiroidismo es una enfermedad que afecta más a las mujeres que a los hombres, con mayor incidencia en la etapa fértil. El diagnóstico y tratamiento oportuno mejoran el pronóstico de la fertilidad, embarazo y vida del recién nacido.
Abstract: OBJECTIVE: To review the most recent bibliography to assess and synthesize the most important aspects in relation to the repercussions of hypothyroidism and its association with infertility in women of reproductive age. METHODOLOGY: Documentary research study carried out based on the search in PubMed and Google Scholar; from the years 1993 to 2018 with the keywords: subclinical hypothyroidism, hypothyroidism, thyroid dysfunction, thyroid hypofunction, subclinical thyroid disease, pregnancy loss, abortion and pregnancy in Spanish and English and retrospective study in textbooks. RESULTS: 39 documents were included, selecting the ones with the highest scientific and epidemiological relevance. Hypothyroidism affects women of reproductive age with a prevalence of 0.4-0.5% for the obvious and 2-8% for the subclinical, the latter can result in female infertility and poor reproductive results. CONCLUSION: Hypothyroidism is a pathology that affects women, with a higher incidence in the fertile stage. A timely diagnosis and treatment improve the prognosis of fertility, pregnancy and life of the newborn.
RESUMO
Protein restriction (PR) during pregnancy induces morphofunctional alterations related to deficient nephrogenesis. We studied the renal functional and morphological significance of PR during pregnancy and/or lactation in adult male rat offspring and the repercussions on acute kidney injury (AKI) severity. Female rats were randomly assigned to the following groups: control diet during pregnancy and lactation (CC), control diet during pregnancy and PR diet during lactation (CR), PR during pregnancy and control diet during lactation (RC), and PR during pregnancy and lactation (RR). Three months after birth, at least 12 male offspring of each group randomly underwent either bilateral renal ischemia for 45 min [ischemia-reperfusion (IR)] or sham surgery. Thus, eight groups were studied 24 h after reperfusion: CC, CC + IR, CR, CR + IR, RC, RC + IR, RR, and RR + IR. Under basal conditions, the CR, RC, and RR groups exhibited a significant reduction in nephron number that was associated with a reduction in renal blood flow. Glomerular hyperfiltration was present as a compensatory mechanism to maintain normal renal function. mRNA levels of several vasoactive, antioxidant, and anti-inflammatory molecules were decreased. After IR, renal function was similarly reduced in all of the studied groups. Although all of the offspring from maternal PR exhibited renal injury, the magnitude was lower in the RC and RR groups, which were associated with faster renal blood flow recovery, differential vasoactive factors, and hypoxia-inducible factor-1α signaling. Our results show that the offspring from maternal PR are resilient to AKI induced by IR that was associated with reduced tubular injury and a differential hemodynamic response.
Assuntos
Injúria Renal Aguda/prevenção & controle , Dieta com Restrição de Proteínas , Injúria Renal Aguda/patologia , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Citocinas/metabolismo , Dieta , Feminino , Taxa de Filtração Glomerular , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Testes de Função Renal , Túbulos Renais/patologia , Lactação , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Circulação Renal , Traumatismo por Reperfusão/prevenção & controleRESUMO
Mineralocorticoid receptor antagonism prevents acute kidney injury induced by ischemia-reperfusion in rodent and pig preclinical models. In a pilot study, we showed that spironolactone (25 mg) reduced oxidative stress after 5 days of kidney transplant (KT). In the present study, we investigated the effects of higher doses (50 and 100 mg) of spironolactone on kidney function, tubular injury markers, and oxidative stress in living donor KT recipients. We included KT recipients aged 18 yr or older who received immunosuppression therapy with IL-2 receptor antagonist, mycophenolate mofetil, corticosteroids, and tacrolimus with negative cross-match, and compatible blood group. Patients were randomized to receive placebo (n = 27), spironolactone (50 mg, n = 25), or spironolactone (100 mg, n = 25). Treatment was given from 3 days before and up to 5 days after KT. Serum creatinine, K+, urine neutrophil gelatinase-associated lipocalin-2, heat shock protein 72, and 8-hydroxy-2-deoxyguanosine levels were assessed. As expected, kidney function was improved after KT. Serum K+ remained in the normal range along the study. There was no significant effect of spironolactone on urinary neutrophil gelatinase-associated lipocalin-2 levels, whereas the increase in urinary heat shock protein 72 levels tended to be less intense in the 100 mg spironolactone-treated group (P = 0.054). In the placebo-treated group, urinary 8-hydroxylated-guanosine levels increased on days 3 and 5 after transplantation. This effect was prevented in patients that received spironolactone. In conclusion, spironolactone reduces the acute increase in urinary oxidative stress in living donor KT recipients.
Assuntos
Antioxidantes/uso terapêutico , Transplante de Rim/métodos , Rim/efeitos dos fármacos , Rim/cirurgia , Doadores Vivos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Espironolactona/uso terapêutico , 8-Hidroxi-2'-Desoxiguanosina/urina , Adulto , Antioxidantes/efeitos adversos , Biomarcadores/sangue , Biomarcadores/urina , Método Duplo-Cego , Feminino , Proteínas de Choque Térmico HSP72/urina , Humanos , Imunossupressores/uso terapêutico , Rim/metabolismo , Rim/fisiopatologia , Transplante de Rim/efeitos adversos , Lipocalina-2/urina , Masculino , México , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Projetos Piloto , Espironolactona/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: We showed that mineralocorticoid receptor blockade (MRB) prevented acute and chronic cyclosporine nephropathy (CsA-Nx) in the rat. The aim of this translational study was to investigate the effect of long-term eplerenone administration on renal allograft function in children with biopsy-proven chronic allograft nephropathy (CAN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal transplant children <18 years, biopsy-proven CAN, and a GFR>40 ml/min per 1.73 m2 were included. Patients with BK virus active nephritis, recurrence of renal disease, GFR decline in previous 3 months, or treated with calcium antagonists or antifungal drugs were excluded. They were randomized to receive placebo (n=10) or eplerenone 25 mg/d for 24 months (n=13). Visits were scheduled at baseline, 6, 12, and 24 months. At each period, a complete clinical examination was performed and blood and urine samples were taken. Urine creatinine, 8-hydroxylated-guanosine, heat shock protein 72 (HSP72), and kidney injury molecule (KIM-1) levels were also assessed. In kidney biopsy samples, the tubulo-interstitial area affected by fibrosis (TIF) and glomerulosclerosis were measured at baseline and after 24 months. RESULTS: The baseline eGFR was 80±6 in the placebo and 86±6 ml/min per 1.73 m2 in the eplerenone group; at 24 months it was 66±8 and 81±7 ml/min per 1.73 m2, respectively (P=0.33; 95% confidence intervals, -18 to 33 at baseline, and -11 to 40 after 24 months). The albumin-to-creatinine ratio was 110±74 in the placebo, and 265±140 mg/g in the eplerenone group; and after 24 months it was 276±140 and 228±88 mg/g, respectively (P=0.15; 95% confidence intervals, -283 to 593, and -485 to 391, respectively). In addition, the placebo exhibited a greater TIF, glomerulosclerosis, and urinary HSP72 compared with the eplerenone group. CONCLUSIONS: Although this study was underpowered to provide definitive evidence that long-term eplerenone administration attenuates the progression of CAN in pediatric transplant patients, it encourages testing the potential benefit of MRB in this pediatric population.