Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.262
Filtrar
1.
Ann Epidemiol ; 41: 7-13.e1, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928894

RESUMO

PURPOSE: We assessed the extent of cardiovascular benefit of renin-angiotensin system (RAS) inhibition beyond lowering blood pressure (BP) and albuminuria in type 1 diabetes (T1D). METHODS: This cohort study included 605 T1D participants from the Pittsburgh Epidemiology of Diabetes Complications study without baseline coronary artery disease (CAD). Participant follow-up extended through 25 years. We implemented marginal structural models to estimate total effect of and controlled direct effect by isolating the role of BP or albuminuria in mediating the relation between RAS inhibitors and CAD. RESULTS: Total effect of longitudinal RAS inhibition treatment was associated with 38% decreased CAD risk (HR [95% CI]: 0.62 [0.23, 1.77]). The controlled direct effect of RAS inhibition was a 27% risk reduction (HR: 0.73 [0.20, 2.59]) when isolating the role of BP and 26% risk reduction (HR: 0.74 [0.16, 3.35]) when isolating the role of albuminuria. The mediation proportion for each 10 mm Hg systolic BP and each 1 log unit of albumin excretion rate were 34% and 37%, respectively. CONCLUSION: Our findings suggest that BP regulation and albuminuria reduction can only partially explain cardiovascular benefit of RAS inhibition on CAD in T1D, supporting the assertion that RAS inhibitors provide additional cardioprotection beyond lowering BP and albuminuria.


Assuntos
Albuminúria/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Prevalência , Resultado do Tratamento
2.
Endocrinol Metab (Seoul) ; 34(4): 398-405, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31884740

RESUMO

BACKGROUND: To evaluate the changes in cardiovascular risk markers including pulse wave velocity (PWV), microalbuminuria, inflammatory cytokines, and adhesion molecules after treatment with beraprost sodium (BPS) in patients with diabetic nephropathy. METHODS: This was a multicenter, prospective, randomized, double-blind, placebo-controlled trial. Type 2 diabetes mellitus patients with microalbuminuria were included. The primary endpoints were changes in microalbuminuria in spot urine and PWV after BPS or placebo (PCB) treatment for 24 weeks. The secondary endpoints were changes in clinical and metabolic parameters. RESULTS: A total of 52 patients completed the 24-week trial. Changes in PWV were not different significantly in the BPS and PCB groups (right, P=0.16; left, P=0.11). Changes in microalbuminuria were 14.2±157.0 and 34.5±146.6 (µg/mg Cr) in the BPS and PCB groups, respectively (P=0.63). Subgroup analysis in the high blood pressure (BP) group (baseline systolic BP >120 mm Hg and diastolic BP >80 mm Hg), showed that microalbuminuria decreased by ?47.6 in the BPS group compared with an increase by 116.4 (µg/mg Cr) in the PCB group (P=0.04). Also, in the large waist circumference group (>95 cm), microalbuminuria decreased significantly in the BPS group (P=0.04). CONCLUSION: Short-term treatment of BPS for patients with diabetic nephropathy did not show significant improvement in various cardiovascular risk factors. However, BPS significantly decreased microalbuminuria in study subjects with higher cardiovascular risk such as high BP or large waist circumference.


Assuntos
Albuminúria/tratamento farmacológico , Biomarcadores/análise , Doenças Cardiovasculares/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Epoprostenol/análogos & derivados , Hipertensão/tratamento farmacológico , Adulto , Idoso , Albuminúria/etiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Nefropatias Diabéticas/epidemiologia , Método Duplo-Cego , Epoprostenol/uso terapêutico , Feminino , Seguimentos , Humanos , Hipertensão/etiologia , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Onda de Pulso , República da Coreia/epidemiologia , Vasodilatadores/uso terapêutico
3.
Drug Des Devel Ther ; 13: 3657-3667, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695333

RESUMO

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established. Methods: Wild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed. Results: Compared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice. Conclusion: Our study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Olmesartana Medoxomila/farmacologia , Albuminúria/tratamento farmacológico , Animais , Creatinina/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Masculino , Camundongos
4.
J Diabetes Res ; 2019: 9415313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781668

RESUMO

Aim: The renoprotective effect of sodium-glucose cotransporter 2 inhibitors is thought to be due, at least in part, to a decrease in blood pressure. The aim of this study was to determine the renal effects of these inhibitors in low blood pressure patients and the dependence of such effect on blood pressure management status. Methods: The subjects of this retrospective study were 740 patients with type 2 diabetes mellitus and chronic kidney disease who had been managed at the clinical facilities of the Kanagawa Physicians Association. Data on blood pressure management status and urinary albumin-creatinine ratio were analyzed before and after treatment. Results: Changes in the logarithmic value of urinary albumin-creatinine ratio in 327 patients with blood pressure < 130/80 mmHg at the initiation of treatment and in 413 patients with BP above 130/80 mmHg were -0.13 ± 1.05 and -0.24 ± 0.97, respectively. However, there was no significant difference between the two groups by analysis of covariance models after adjustment of the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment. Changes in the logarithmic value of urinary albumin-creatinine ratio in patients with mean blood pressure of <102 mmHg (n = 537) and those with ≥102 mmHg (n = 203) at the time of the survey were -0.25 ± 1.02 and -0.03 ± 0.97, respectively, and the difference was significant in analysis of covariance models even after adjustment for the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment (p < 0.001). Conclusion: Our results confirmed that blood pressure management status after treatment with SGLT2 inhibitors influences the extent of change in urinary albumin-creatinine ratio. Stricter blood pressure management is needed to allow the renoprotective effects of sodium-glucose cotransporter 2 inhibitors.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Albuminúria/tratamento farmacológico , Albuminúria/epidemiologia , Albuminúria/fisiopatologia , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Japão/epidemiologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
5.
J. bras. nefrol ; 41(3): 315-322, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040245

RESUMO

Abstract Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.


Resumo Introdução: Supõe-se que elevações da expressão do fator de inibição da migração de macrófagos (MIF) possam contribuir para a patogênese da nefropatia diabética (ND). O objetivo do presente estudo foi investigar os efeitos renais da inibição do MIF em um modelo experimental diabético. Métodos: Dezoito ratos Wistar machos (230 ± 20g) foram divididos em três grupos: 1) controle, 2) diabético (STZ 50 mg/kg dissolvida em soro fisiológico, IP), 3) diabético + antagonista do MIF (p425 1 mg/kg por dia IP no 21o dia por 21 dias consecutivos). O tratamento começou após a identificação de aumento significativo na albuminúria nos ratos diabéticos em relação aos controles. Os ratos foram mantidos individualmente em gaiolas metabólicas (8h-14h) e amostras de urina foram colhidas no 21o e no 42o dia. Ao final do estudo, amostras de sangue e tecido foram colhidas para análises bioquímicas (BS, excreção urinária de proteína, excreção urinária de GAGs, BUN, Cr, Na e K) e histológicas. Resultados: O presente estudo demonstrou que o antagonista do MIF (p425) diminuiu significativamente proteinúria, excreção urinária de GAGs , relação proteína/creatinina na urina, BUN e Cr no grupo com ND induzida por estreptozotocina. As alterações patológicas foram significativamente abrandadas nos ratos com ND que receberam antagonista do MIF (p425). Conclusão: Coletivamente, os dados sugerem que o antagonista do MIF (p425) teve efeito protetor contra lesões funcionais e histopatológicas da ND.


Assuntos
Animais , Masculino , Ratos , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Oxirredutases Intramoleculares/antagonistas & inibidores , Substâncias Protetoras/uso terapêutico , Substâncias Protetoras/farmacologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/terapia , Glicemia , Ratos Wistar , Estreptozocina/farmacologia , Creatinina/urina , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Experimental/sangue , Nefropatias Diabéticas/urina , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/sangue , Albuminúria/tratamento farmacológico , Modelos Animais de Doenças , Glicosaminoglicanos/urina , Rim/patologia , Ativação de Macrófagos
6.
Cardiovasc Diabetol ; 18(1): 110, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455298

RESUMO

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Albuminúria/fisiopatologia , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/metabolismo , Humanos , Japão/epidemiologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Nat Commun ; 10(1): 3656, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409793

RESUMO

In this work we model the glomerular filtration barrier, the structure responsible for filtering the blood and preventing the loss of proteins, using human podocytes and glomerular endothelial cells seeded into microfluidic chips. In long-term cultures, cells maintain their morphology, form capillary-like structures and express slit diaphragm proteins. This system recapitulates functions and structure of the glomerulus, including permselectivity. When exposed to sera from patients with anti-podocyte autoantibodies, the chips show albuminuria proportional to patients' proteinuria, phenomenon not observed with sera from healthy controls or individuals with primary podocyte defects. We also show its applicability for renal disease modeling and drug testing. A total of 2000 independent chips were analyzed, supporting high reproducibility and validation of the system for high-throughput screening of therapeutic compounds. The study of the patho-physiology of the glomerulus and identification of therapeutic targets are also feasible using this chip.


Assuntos
Glomérulos Renais/metabolismo , Dispositivos Lab-On-A-Chip , Nefrite Hereditária/metabolismo , Albuminas/metabolismo , Albuminúria/tratamento farmacológico , Albuminúria/metabolismo , Células Imobilizadas/química , Células Imobilizadas/metabolismo , Células Endoteliais/química , Células Endoteliais/metabolismo , Humanos , Glomérulos Renais/química , Glomérulos Renais/efeitos dos fármacos , Masculino , Nefrite Hereditária/tratamento farmacológico , Podócitos/química , Podócitos/metabolismo
9.
Proc Natl Acad Sci U S A ; 116(28): 14154-14163, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235574

RESUMO

Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS.


Assuntos
Cálcio/metabolismo , Síndrome Nefrótica/genética , Fatores de Crescimento Neural/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Albuminúria/tratamento farmacológico , Albuminúria/genética , Albuminúria/patologia , Animais , Sinalização do Cálcio/genética , Calpaína/genética , Modelos Animais de Doenças , Retículo Endoplasmático/genética , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/genética , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Camundongos , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/patologia , Podócitos/metabolismo , Podócitos/patologia , Talina/genética , Tiazepinas/farmacologia
10.
Diabetologia ; 62(9): 1575-1580, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31154479

RESUMO

AIMS/HYPOTHESIS: Epidemiological studies have shown that diabetes is a well-established independent but modifiable risk factor for stroke. The aim of this post hoc analysis of data from the Steno-2 Study was to examine whether multiple risk factor intervention reduced the risk for stroke in individuals with type 2 diabetes and microalbuminuria. METHODS: In the Steno-2 Study, 160 individuals with type 2 diabetes and microalbuminuria were randomised to intensified or conventional multiple risk factor intervention, targeting classical cardiovascular disease risk factors for a mean of 7.8 years, and then followed for a total mean of 21.2 years. The primary endpoint in this post hoc analysis was time to first stroke event. RESULTS: During follow-up, 30 participants experienced a total of 39 strokes. Individuals randomised to conventional therapy were more likely to experience a stroke than those in the intensive-therapy group, with 29 total strokes occurring in 21 participants (26%) in the conventional-therapy group vs a total of ten strokes in nine participants (11%) in the intensive-therapy group (HR 0.31 [95% CI 0.14, 0.69]; p = 0.004). Also, the number of recurrent strokes was significantly reduced with intensive therapy. CONCLUSIONS/INTERPRETATION: Intensified multiple risk factor intervention in patients with type 2 diabetes and microalbuminuria reduces the risk for strokes as well as the number of recurrent cerebrovascular events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00320008.


Assuntos
Terapia Combinada/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/terapia , Albuminúria/tratamento farmacológico , Albuminúria/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/terapia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Fatores de Risco
11.
Circ Heart Fail ; 12(6): e005875, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31163986

RESUMO

Background In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin significantly reduced the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus and established cardiovascular disease. Post hoc, we evaluated empagliflozin on kidney outcomes in patients with or without heart failure (HF). Methods and Results Individuals were randomized to empagliflozin 10 mg, 25 mg, or placebo. Prespecified analyses by baseline HF status included risk of incident or worsening nephropathy and estimated glomerular filtration rate slope analyses. Cox proportional hazards models assessed consistency of treatment effect across subgroups. Safety evaluations included kidney-related adverse events. At baseline, 244 (10.5%) and 462 (9.9%) patients had HF in the placebo and empagliflozin groups, respectively. Overall, the incidence of kidney outcome events was numerically higher in patients with than without HF. In the HF group, empagliflozin reduced risk of incident or worsening nephropathy or cardiovascular death by 43% (hazard ratio, 0.57 [95% CI, 0.42-0.77]) and progression to macroalbuminuria by 50% (hazard ratio, 0.50 [0.33-0.75]). After an initial transient decrease, estimated glomerular filtration rate stabilized over time with empagliflozin but gradually declined with placebo. Kidney effects in patients with HF were consistent with those in the overall study population (all P values for interaction >0.05). Across groups, the incidence rate of kidney-related adverse events/100 patient-years was higher in patients with than without HF; however, overall rates were comparable between groups. Conclusions These findings from EMPA-REG OUTCOME support the hypothesis that empagliflozin could reduce the risk of clinically relevant kidney events and may slow progression of chronic kidney disease in individuals with type 2 diabetes mellitus regardless of HF status. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Adulto , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
12.
Diabetes Care ; 42(8): 1454-1463, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31186299

RESUMO

OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.


Assuntos
Alopurinol/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Ácido Úrico/sangue , Idoso , Albuminúria/tratamento farmacológico , Albuminúria/etiologia , Albuminúria/fisiopatologia , Pressão Sanguínea , Diabetes Mellitus Tipo 1/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Risco
13.
Am Fam Physician ; 99(12): 751-759, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194487

RESUMO

Globally, approximately 20% of the 400 million individuals with diabetes mellitus have diabetic kidney disease (DKD). DKD is associated with higher cardiovascular and all-cause morbidity and mortality, so timely diagnosis and treatment are critical. Screening for early DKD is best done with annual spot urine albumin/creatinine ratio testing, and diagnosis is confirmed by repeated elevation in urinary albumin excretion. Treatment includes management of hyperglycemia, hypertension, hyperlipidemia, and cessation of tobacco use. Multiple antihyperglycemic medications, including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl-peptidase-4 inhibitors, may help prevent DKD by lowering blood glucose levels and through intrinsic renal protection. Blood pressure should be monitored at every clinical visit and maintained at less than 140/90 mm Hg to prevent microvascular changes. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent progression of DKD and may decrease albuminuria. Statin therapy should be considered for all patients with DKD, and tobacco cessation reduces the risk of DKD. Given the complexity of the disease and the risk of poor outcomes, patients who progress to stage 3 DKD or beyond may benefit from referral to nephrology subspecialists.


Assuntos
Albuminúria/diagnóstico , Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Guias de Prática Clínica como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Currículo , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/etiologia , Educação Médica Continuada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Nat Commun ; 10(1): 1835, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015435

RESUMO

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.


Assuntos
Albuminúria/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Microbioma Gastrointestinal/fisiologia , Ésteres do Ácido Sulfúrico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/sangue , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Cães , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Podócitos/metabolismo , Podócitos/patologia , Ratos , Estreptozocina/toxicidade , Ésteres do Ácido Sulfúrico/sangue , Tirosina Fenol-Liase/antagonistas & inibidores , Tirosina Fenol-Liase/metabolismo , Adulto Jovem
15.
Cardiovasc Diabetol ; 18(1): 33, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-30878037

RESUMO

BACKGROUND: To evaluate the characteristics of type 2 diabetes (T2DM) patients with or without chronic kidney disease (CKD) in Germany. METHODS: Using combined DPV/DIVE registry data, the analysis included patients with T2DM at least ≥ 18 years old who had an estimated glomerular filtration rate (eGFR) value available. CKD was defined as an eGFR < 60 mL/min/1.73 m2 or eGFR ≥ 60 mL/min/1.73 m2 and albuminuria (≥ 30 mg/g). Median values of the most recent treatment year per patient are reported. RESULTS: Among 343,675 patients with T2DM 171,930 had CKD. Patients with CKD had a median eGFR of 48.9 mL/min/1.73 m2 and 51.2% had a urinary albumin level ≥ 30 mg/g. They were older, had a longer diabetes duration and a higher proportion was females compared to patients without CKD (all p < 0.001). More than half of CKD patients (53.5%) were receiving long-acting insulin-based therapy versus around 39.1% of those without (p < 0.001). CKD patients also had a higher rate of hypertension (79.4% vs 72.0%; p < 0.001). The most common antihypertensive drugs among CKD patients were renin-angiotensin-aldosteron system inhibitors (angiotensin converting enzyme inhibitors 33.8%, angiotensin receptor blockers 14.2%) and diuretics (40.2%). CKD patients had a higher rate of dyslipidemia (88.4% vs 86.3%) with higher triglyceride levels (157.9 vs 151.0 mg/dL) and lower HDL-C levels (men: 40.0 vs 42.0 mg/dL; women: 46.4 vs 50.0 mg/dL) (all p < 0.001) and a higher rate of hyperkalemia (> 5.5 mmol/L: 3.7% vs. 1.0%). Comorbidities were more common among CKD patients (p < 0.001). CONCLUSION: The results illustrate the prevalence and morbidity burden associated with diabetic kidney disease in patients with T2DM in Germany. The data call for more attention to the presence of chronic kidney disease in patients with diabetes, should trigger intensified risk factor control up and beyond the control of blood glucose and HbA1c in these patients. They may also serve as a trigger for future investigations into this patient population asking for new treatment options to be developed.


Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Fatores Etários , Idoso , Albuminúria/diagnóstico , Albuminúria/tratamento farmacológico , Albuminúria/fisiopatologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Áustria/epidemiologia , Comorbidade , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Diuréticos/uso terapêutico , Feminino , Alemanha/epidemiologia , Taxa de Filtração Glomerular , Humanos , Hipoglicemiantes/uso terapêutico , Rim/fisiopatologia , Luxemburgo/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores Sexuais
16.
Ann Biol Clin (Paris) ; 77(1): 10-12, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30799290

RESUMO

Today, medical prescriptions of proteinuria or albuminuria, which are depending on medical status of patients, still depend on doctors. Indeed, according to their medical specialty or to the recommendations they are following, they could prescribe either proteinuria or albuminuria. The consequences are practical for laboratories and economical for patients and doctors. This article resumes different situations, which result in an erroneous interpretation of medical prescriptions.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Prescrições/estatística & dados numéricos , Proteinúria/tratamento farmacológico , Proteinúria/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/tratamento farmacológico , Albuminúria/epidemiologia , Feminino , Humanos , Masculino , Erros de Medicação/estatística & dados numéricos , Medicina/estatística & dados numéricos , Pessoa de Meia-Idade , Médicos/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Gravidez , Prescrições/normas , Adulto Jovem
17.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1332-1340, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30763641

RESUMO

Diabetic nephropathy (DN) is one of the major long-term complications of diabetes. Lysophosphatidic acid (LPA) signaling has been implicated in renal fibrosis. In our previous study, we found that the LPA receptor 1/3 (LPAR1/3) antagonist, ki16425, protected against DN in diabetic db/db mice. Here, we investigated the effects of a specific pharmacological inhibitor of LPA receptor 1 (LPA1), AM095, on DN in streptozotocin (STZ)-induced diabetic mice to exclude a possible contribution of LPAR3 inhibition. AM095 treatment significantly reduced albuminuria and the albumin to creatinine ratio and significantly decreased the glomerular volume and tuft area in the treated group compared with the STZ-vehicle group. In the kidney of STZ-induced diabetic mice, the expression of LPAR1 mRNA and protein was positively correlated with oxidative stress. AM095 treatment inhibited LPA-induced reactive oxygen species production and NADPH oxidase expression as well as LPA-induced toll like receptor 4 (TLR4) expression in mesangial cells and in the kidney of STZ-induced diabetic mice. In addition, AM095 treatment suppressed LPA-induced pro-inflammatory cytokines and fibrotic factors expression through downregulation of phosphorylated NFκBp65 and c-Jun N-terminal kinases (JNK) in vitro and in the kidney of STZ-induced diabetic mice. Pharmacological or siRNA inhibition of TLR4 and NADPH oxidase mimicked the effects of AM095 in vitro. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN.


Assuntos
Antioxidantes/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fenilacetatos/farmacologia , Receptores de Ácidos Lisofosfatídicos/genética , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/genética , Albuminúria/induzido quimicamente , Albuminúria/tratamento farmacológico , Albuminúria/genética , Albuminúria/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Estreptozocina , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismo
18.
Int Urol Nephrol ; 51(4): 755-764, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30734886

RESUMO

PURPOSE: Podocytes are terminally differentiated cells lining the Bowman's capsule. Podocytes are critical for the proper glomerular filtration barrier function. At the same time, autophagy is crucial for maintaining podocyte homeostasis and insufficient autophagy could cause podocyte loss and proteinuria that is commonly observed in diabetic nephropathy (DN). METHODS: In this study, we investigated the role of spironolactone in podocyte loss and autophagy. DN model was established in male Sprague-Dawley rats using high-fat diet and low-dose streptozotocin. The impact of spironolactone on metabolic and biochemical parameters were tested by automatic biochemical analyzer. The angiotensin converting enzyme 1 and 2 (ACE1 and ACE2) and aldosterone were examined by ELISA. We examined the kidney histology and autophagy in podocytes by histochemical staining and electron microscopy. Podocyte loss and autophagy were analyzed by anti-NPHS2 and anti-WT1 as well as anti-Beclin1 and anti-LC3B, respectively. RESULTS: Spironolacton decreased the urinary albumin excretion, lipids and fasting glucose levels, and alleviated kidney damage. Further, spironolactone increased the expression of the podocyte-specific markers WT1 and NPHS2, as well as the autophagic markers Beclin1 and LC3B (P < 0.05). Additionally, spironolactone partially blocked the rennin angiotensin aldosterone system (RAAS) by regulating the ACE1, ACE2 and aldosterone levels. CONCLUSIONS: In conclusion, spironolactone promoted autophagy in podocytes and further alleviated DN through partially blocking the RAAS.


Assuntos
Autofagia/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Podócitos , Espironolactona/uso terapêutico , Albuminúria/tratamento farmacológico , Aldosterona/metabolismo , Animais , Proteína Beclina-1/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/farmacologia , Proteínas WT1/metabolismo
19.
J Bras Nefrol ; 41(3): 315-322, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30720852

RESUMO

INTRODUCTION: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. METHODS: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. RESULTS: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. CONCLUSION: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.


Assuntos
Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Oxirredutases Intramoleculares/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Azul Tripano/farmacologia , Azul Tripano/uso terapêutico , Albuminúria/tratamento farmacológico , Animais , Glicemia , Creatinina/sangue , Creatinina/urina , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Modelos Animais de Doenças , Glicosaminoglicanos/urina , Rim/patologia , Ativação de Macrófagos , Masculino , Ratos , Ratos Wistar , Estreptozocina/farmacologia
20.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1313-1322, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710617

RESUMO

Activation of the renin-angiotensin system (RAS) plays a pivotal role in mediating hypertension, chronic kidney and cardiovascular diseases. As Wnt/ß-catenin regulates multiple RAS genes, we speculated that this developmental signaling pathway might also participate in blood pressure (BP) regulation. To test this, we utilized two rat models of experimental hypertension: chronic angiotensin II infusion and remnant kidney after 5/6 nephrectomy. Inhibition of Wnt/ß-catenin by ICG-001 blunted angiotensin II-induced hypertension. Interestingly, angiotensin II was able to induce the expression of multiple Wnt genes in vivo and in vitro, thereby creating a vicious cycle between Wnt/ß-catenin and RAS activation. In the remnant kidney model, renal ß-catenin was upregulated, and delayed administration of ICG-001 also blunted BP elevation and abolished the induction of angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II type 1 receptor. ICG-001 also reduced albuminuria, serum creatinine and blood urea nitrogen, and inhibited renal expression of fibronectin, collagen I and plasminogen activator inhibitor-1, and suppressed the infiltration of CD3+ T cells and CD68+ monocytes/macrophages. In vitro, incubation with losartan prevented Wnt/ß-catenin-mediated fibronectin, α-smooth muscle actin and Snail1 expression, suggesting that the fibrogenic action of Wnt/ß-catenin is dependent on RAS activation. Taken together, these results suggest an intrinsic linkage of Wnt/ß-catenin signaling with BP regulation. Our studies also demonstrate that hyperactive Wnt/ß-catenin can drive hypertension and kidney damage via RAS activation.


Assuntos
Albuminúria/genética , Hipertensão/genética , Rim/metabolismo , Proteínas Wnt/genética , beta Catenina/genética , Albuminúria/tratamento farmacológico , Albuminúria/etiologia , Albuminúria/fisiopatologia , Angiotensina II/administração & dosagem , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Creatinina/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Nefrectomia/métodos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirimidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA