RESUMO
Our research has shown that interventions producing a state of ketosis are highly effective in rat, mouse, and cat models of polycystic kidney disease (PKD), preventing and partially reversing cyst growth and disease progression. The ketone ß-hydroxybutyrate (BHB) appears to underlie this effect. In addition, we have demonstrated that naturally formed microcrystals within kidney tubules trigger a renoprotective response that facilitates tubular obstruction clearance in healthy animals but, alternatively, leads to cyst formation in PKD. The administration of citrate prevents microcrystal formation and slows PKD progression. Juvenile Cy/+ rats, a nonorthologous PKD model, were supplemented from 3 to 8 wk of age with water containing titrated BHB, citrate, or in combination to find minimal effective and optimal dosages, respectively. Adult rats were given a reduced BHB/citrate combination or equimolar control K/NaCl salts from 8 to 12 wk of age. In addition, adult rats were placed in metabolic cages following BHB, citrate, and BHB/citrate administration to determine the impact on mineral, creatinine, and citrate excretion. BHB or citrate alone effectively ameliorates disease progression in juvenile rats, decreasing markers of cystic disease and, in combination, producing a synergistic effect. BHB/citrate leads to partial disease regression in adult rats with established cystic disease, inhibiting cyst formation and kidney injury. BHB/citrate confers benefits via multiple mechanisms, increases creatinine and citrate excretion, and normalizes mineral excretion. BHB and citrate are widely available and generally recognized as safe compounds and, in combination, exhibit high promise for supporting kidney health in polycystic kidney disease.NEW & NOTEWORTHY Combining ß-hydroxybutyrate (BHB) and citrate effectively slows and prevents cyst formation and expansion in young Cy/+ rats using less BHB and citrate than when used alone, demonstrating synergy. In adult rats, the combination causes a partial reversal of existing disease, reducing cyst number and cystic area, preserving glomerular health, and decreasing markers of kidney injury. Our results suggest a safe and feasible strategy for supporting kidney health in polycystic kidney disease (PKD) using a combination of BHB and citrate.
Assuntos
Cistos , Doenças Renais Policísticas , Animais , Ratos , Ácido 3-Hidroxibutírico/farmacologia , Citratos/farmacologia , Citratos/uso terapêutico , Ácido Cítrico , Creatinina , Modelos Animais de Doenças , Progressão da Doença , Minerais , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/metabolismoRESUMO
Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Triterpenos Pentacíclicos/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Animais , Cistos/patologia , Cistos/fisiopatologia , Testes de Função Renal , Camundongos , Triterpenos Pentacíclicos/farmacologia , Fenótipo , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/fisiopatologia , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
BACKGROUND: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized -Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. METHODS: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. RESULTS: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. CONCLUSION: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.
Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Animais , Masculino , Ratos , Resultado do TratamentoRESUMO
Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by â¼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement.
Assuntos
Cálcio da Dieta/farmacologia , Doenças Cardiovasculares/complicações , Colecalciferol/farmacologia , Rim/patologia , Doenças Renais Policísticas/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Animais , Colecalciferol/sangue , Suplementos Nutricionais , Progressão da Doença , Masculino , Fosfatos/sangue , Doenças Renais Policísticas/complicações , Proteinúria , Ratos , Ratos Endogâmicos Lew , Deficiência de Vitamina D/complicaçõesAssuntos
Benzenossulfonatos/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridinas/uso terapêutico , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Doenças Renais Policísticas/patologia , Sorafenibe , TolvaptanRESUMO
Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.
Assuntos
Hipoglicemiantes/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Animais , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Modelos Animais de Doenças , Progressão da Doença , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Masculino , PPAR gama/agonistas , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Rosiglitazona , Análise de Sobrevida , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/genéticaRESUMO
Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC(50) approximately 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Cistos/patologia , Doenças Renais Policísticas/patologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Animais , Linhagem Celular , Cistos/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Doenças Renais Policísticas/tratamento farmacológico , Quinoxalinas/síntese química , Quinoxalinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
Increasing evidence in human chronic kidney disease and in animal models indicates the potential utility of dietary soy protein in the treatment of this disorder. A model in which a beneficial soy protein effect has been consistently demonstrated is the Han:SPRD-cy rat model of polycystic kidney disease. Therefore, since dietary soy protein alters renal hemodynamics and prostanoid production, the effects of dietary soy protein on renal prostanoids and related rate-limiting enzymes were examined. Normal and diseased weanling rats were given diets containing casein or soy protein for 7 wk. At 10 wk of age, renal levels of thromboxane B(2) (TXB(2), stable metabolite of TXA(2)), prostaglandin E(2) (PGE(2)) and 6-keto PGF(1alpha) (stable metabolite of PGI(2)) and activities of cyclooxygenase 1 (COX1) and COX2 were elevated in diseased compared to normal kidneys. Soy protein feeding resulted in 49% lower in vitro steady-state levels of TXB(2), and 76% less 6-keto PGF(1alpha) produced by COX1 activity in diseased kidneys, while not altering these parameters in normal kidneys. It also resulted in 47% less TXB(2) and 36% lower 6-keto PGF(1alpha) produced by COX2 activity in diseased kidneys. The relative effect of soy protein feeding on COX2 activity was in the order of TXB(2) > 6-keto PGF(1alpha) > PGE(2). Diseased kidneys had elevated protein and mRNA levels of cytosolic phospholipase A(2) (cPLA(2)) and COX1 and lower levels of COX2. Dietary soy protein attenuated the protein levels of cPLA(2) in diseased kidneys, and reduced COX2 mRNA expression in both normal and diseased kidneys. Dietary soy protein therefore reduced the levels of specific renal prostanoids, cPLA(2) and COX enzymes in this model of polycystic kidney disease, a model in which soy protein has been demonstrated to reduce disease progression.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Rim/metabolismo , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/metabolismo , Prostaglandinas/metabolismo , Proteínas de Soja/uso terapêutico , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Dinoprostona/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Rim/efeitos dos fármacos , Masculino , Fosfolipases A2/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Mutantes , Proteínas de Soja/farmacologia , Tromboxano B2/metabolismoRESUMO
A common cause of kidney failure is autosomal dominant polycystic kidney disease (ADPKD). It is characterized by the growth of cysts in the kidneys and hence the growth of the entire kidneys with eventual failure in most cases by age 50. No preventive treatment for this condition is available. Preclinical drug treatment studies use an in vivo mouse model of the condition. The analysis of mice imaging data for such studies typically requires extensive manual interaction, which is subjective and not reproducible. In this work both untreated and treated mice have been imaged with a high field, 9.4T, MRI animal scanner and a reliable algorithm for the automated segmentation of the mouse kidneys has been developed. The algorithm first detects the region of interest (ROI) in the image surrounding the kidneys. A parameterized geometric shape for a kidney is registered to the ROI of each kidney. The registered shapes are incorporated as priors to the graph cuts algorithm used to extract the kidneys. The accuracy of the automated segmentation has been demonstrated by comparing it with a manual segmentation. The processing results are also consistent with the literature for previous techniques.
Assuntos
Modelos Animais de Doenças , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Morfolinas/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/patologia , Compostos de Espiro/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
Conjugated linoleic acid (CLA) is anti-proliferative and anti-inflammatory in the Han:SPRD-cy rat model of kidney disease. We used different doses of CLA and examined effects on renal histological benefit, the renal PPARgamma system and hepatic and renal levels of CLA isomers. Male and female offspring of Han:SPRD-cy heterozygotes were fed diets with 0, 1 or 2% CLA isomer mixture for 12 weeks before dual-energy X-ray absorptiometry, harvest of renal and hepatic tissue for histologic and lipid analysis. Both CLA diets reduced body fat content in both genders but did not change lean body mass. CLA produced a dose dependent reduction in female renal cystic change. CLA reduced fibrosis, but this reduction was significantly less with higher dose in males. CLA reduced macrophage infiltration, tissue oxidized LDL content and proliferation of epithelial cells. Serum creatinine rose significantly in female animals fed CLA diets. CLA treatment did not change PPARgamma activation. A significant negative correlation with renal content of the 18:2 c9,t11 isomer and the sum of histologic effects was identified. CLA reduces histologic renal injury in the Han:SPRD-cy rat model probably inversely proportionate to c9,t11 renal content. Possible functional CLA toxicity at high dose in female animals warrants further exploration.
Assuntos
Gorduras na Dieta/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , Animais , Composição Corporal , Densidade Óssea , Creatinina/sangue , Gorduras na Dieta/toxicidade , Feminino , Isomerismo , Rim/química , Rim/patologia , Ácidos Linoleicos Conjugados/toxicidade , Fígado/química , Masculino , Doenças Renais Policísticas/tratamento farmacológico , Ratos , Fatores SexuaisRESUMO
Increased cell proliferation and fluid secretion, probably driven by alterations in intracellular calcium homeostasis and cyclic adenosine 3,5-phosphate, play an important role in the development and progression of polycystic kidney disease. Hormone receptors that affect cyclic adenosine monophosphate and are preferentially expressed in affected tissues are logical treatment targets. There is a sound rationale for considering the arginine vasopressin V2 receptor as a target. The arginine vasopressin V2 receptor antagonists OPC-31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease (PCK rat), autosomal dominant polycystic kidney disease (Pkd2/WS25 mice), and nephronophthisis (pcy mouse). PCK rats that are homozygous for an arginine vasopressin mutation and lack circulating vasopressin are markedly protected. Administration of V2 receptor agonist 1-deamino-8-D-arginine vasopressin to these animals completely recovers the cystic phenotype. Administration of 1-deamino-8-D-arginine vasopressin to PCK rats with normal arginine vasopressin aggravates the disease. Suppression of arginine vasopressin release by high water intake is protective. V2 receptor antagonists may have additional beneficial effects on hypertension and chronic kidney disease progression. A number of clinical studies in polycystic kidney disease have been performed or are currently active. The results of phase 2 and phase 2-3 clinical trials suggest that tolvaptan is safe and well tolerated in autosomal dominant polycystic kidney disease. A phase 3, placebo-controlled, double-blind study in 18- to 50-yr-old patients with autosomal dominant polycystic kidney disease and preserved renal function but relatively rapid progression, as indicated by a total kidney volume >750 ml, has been initiated and will determine whether tolvaptan is effective in slowing down the progression of this disease.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Doenças Renais Policísticas/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Doenças Renais Policísticas/etiologia , Vasopressinas/fisiologiaAssuntos
Arginina Vasopressina/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Recessivo/tratamento farmacológico , Vasopressinas/uso terapêutico , Humanos , Doenças Renais Policísticas/fisiopatologia , Rim Policístico Autossômico Dominante/fisiopatologia , Rim Policístico Autossômico Recessivo/fisiopatologiaRESUMO
During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca(2+) release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca(2+) signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Doenças Renais Policísticas/tratamento farmacológico , Canais de Cátion TRPP/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Células Epiteliais/citologia , Compostos de Epóxi/farmacologia , Imunossupressores/farmacologia , Rim/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Transgenes , Quinases Ativadas por p21RESUMO
AVI BioPharma is developing AVI-4126, an antisense oligonucleotide targeted to c-myc mRNA for the potential treatment of restenosis, cancer and polycystic kidney disease. AVI-4126 is currently undergoing phase II clinical trials.
Assuntos
Genes myc/genética , Morfolinas/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Reestenose Coronária/tratamento farmacológico , Reestenose Coronária/genética , Avaliação Pré-Clínica de Medicamentos , Genes myc/fisiologia , Humanos , Morfolinas/efeitos adversos , Morfolinas/síntese química , Morfolinas/farmacocinética , Morfolinos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/síntese química , Oligonucleotídeos Antissenso/farmacocinética , Patentes como Assunto , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/genética , Relação Estrutura-AtividadeRESUMO
Low-fat diets and diets containing n-3 fatty acids (FA) slow the progression of renal injury in the male Han:Sprague-Dawley (SPRD)-cy rat model of polycystic kidney disease. To determine whether these dietary fat effects are similar in females and in another model of renal cystic disease, in this study we used both male and female pcy mice to examine the effects of fat level and type on disease progression. Adult pcy mice were fed 4, 10, or 20 g soybean oil/100 g diet for 130 d in study 1. In study 2, weanling pcy mice were fed high or low levels of fat rich in 18:2n-6 (corn oil, CO), 18:3n-3 (flaxseed oil/CO 4:1 g/g, FO), or 22:6n-3 (algal oil/CO 4:1 g/g, DO) for 8 wk. In adult pcy mice, low- compared with high-fat diets lowered kidney weights (2.4 +/- 0.2 vs. 3.1 +/- 0.2 g/100 g body weight, P = 0.006) and serum urea nitrogen (SUN) (9.6 +/- 0.6 vs. 11.9 +/- 0.6 mmol/L, P = 0.009), whereas in young pcy mice it reduced renal fibrosis volumes (0.44 +/- 0.04 vs. 0.62 +/- 0.04 mL/kg body weight, P < 0.0001). FO feeding in young pcy mice mitigated the detrimental effects of high fat on fibrosis while not altering kidney size, function, and oxidative damage when compared with the CO-fed mice. In contrast, DO- compared with CO-fed mice had higher kidney weights (2.64 +/- 0.07 vs. 2.24 +/- 0.08 g/100 g body weight, P = 0.005), SUN (9.4 +/- 0.57 vs. 7.0 +/- 0.62 mmol/L, P < 0.0001), and cyst volumes (7.9 +/- 0.28 vs. 6.2 +/- 0.30 mL/kg body weight, P < 0.0001) and similar levels of oxidative damage and fibrosis. The FA compositions of the diets were reflected in the kidneys: 18:2n-6, 18:3n-3, and 22:6n-3 were the highest in the CO, FO, and DO diets, respectively. Dietary effects on kidney disease progression were similar in males and females. A low-fat diet slows progression of renal injury in male and female pcy mice, consistent with findings in the male Han:SPRD-cy rat. Dietary fat type also influenced renal injury, with flaxseed oil diets rich in 18:3n-3 slowing early fibrosis progression compared with diets rich in 18:2n-6 or in 22:6n-3.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Proteínas/genética , Ração Animal , Animais , Óleo de Milho/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos/análise , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/química , Feminino , Fibrose , Rim/química , Rim/patologia , Óleo de Semente do Linho/farmacologia , Masculino , Camundongos , Camundongos Mutantes , Tamanho do Órgão , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , Canais de Cátion TRPPRESUMO
The childhood forms of polycystic kidney disease are autosomal recessive polycystic kidney disease and nephronophthisis. In animal models of these diseases, characterised by a defect in urine concentration progressing to renal failure, the selective vasopressin receptor type 2 antagonist OPC-31260 halted the progression or even caused regression of the established disease. Vasopressin receptor type 2 antagonists should proceed to clinical trial for these polycystic kidney diseases.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Animais , Benzazepinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , HumanosRESUMO
BACKGROUND: We reported a lessened cyst growth in the pcy mouse model of polycystic kidney disease (PKD) when mice were fed a soy protein isolate (SPI)-based diet and hypothesized that the soyasaponins may be associated with this therapeutic effect. The effects of feeding a saponin-enriched alcohol extract (SEAE) from SPI, an isoflavone- and saponin-enriched soy supplement (Novasoy 400), or a 99.5% pure soyasaponin Bb powder on cyst growth are reported here. METHODS: The therapeutic effects of the soyasaponins were studied in 60-day-old male pcy mice in two separate, 90-day feeding trials. In the first study, mice were fed either a casein-based (control) diet, a diet in which SPI replaced the casein or the control diet supplemented with SEAE. In the second study, mice were fed the control diet unsupplemented or supplemented with either a soyasaponin- and isoflavone-enriched soy product (Novasoy 400) or a 99.5% pure soyasaponin Bb powder. RESULTS: In study 1, kidney weight, water content, and plasma creatinine and urea levels were markedly reduced in the SEAE-fed animals compared to tissues from the control group; likewise, mice fed the SPI-based diet showed a decreased plasma creatinine, but only a slightly reduced plasma urea. In study 2, kidney weight, water content, plasma creatinine and urea levels were significantly reduced in mice fed the soyasaponin Bb powder and the Novasoy-400 supplement, compared to controls. CONCLUSION: Soyasaponin Bb can impede kidney enlargement and cyst growth in the pcy mouse model of PKD. Further studies are needed to determine its most effective dose and mechanism of action.
Assuntos
Doenças Renais Policísticas/tratamento farmacológico , Saponinas/farmacologia , Proteínas de Soja/farmacologia , Ração Animal , Animais , Peso Corporal/efeitos dos fármacos , Caseínas/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Isoflavonas/farmacologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Mutantes , Tamanho do Órgão/efeitos dos fármacos , Doenças Renais Policísticas/patologia , Saponinas/química , Proteínas de Soja/química , Água/metabolismoRESUMO
As whole flaxseed is beneficial in the treatment of experimental renal disease, we undertook a study to determine whether previously documented benefits of whole flaxseed could be reproduced with dietary low-lignan flax oil (FO), a rich source of alpha-linolenic acid, in experimental polycystic kidney disease. Male offspring of Han:SPRD-cy heterozygous rats were fed a synthetic diet containing FO or corn oil (CO) for 8 wk from the time of weaning. Renal inflammation, fibrosis, proliferation, cystic change, and oxidized-LDL were assessed morphometrically. Hepatic and renal lipid composition was assessed using GC. FO feeding produced hepatic and renal enrichment of n-3 PUFA and an increase in C18:>C18 PUFA ratios (18-carbon PUFA compared to longer-chain PUFA), with a reduction in proportion of hepatic long-chain PUFA. The FO-based diet was associated with lower mean cystic change by 29.7% (P = 0.018), fibrosis by 21.7% (P = 0.017), macrophage infiltration by 31.5% (P < 0.0001), epithelial proliferation by 18.7% (P = 0.0035), and ox-LDL detection by 31.4% (P < 0.0001) in Han:SPRD-cy heterozygotes. Serum creatinine was significantly lower in FO-fed diseased animals. A small hypocholesterolemic effect was noted in all animals fed FO. FO feeding moderates renal injury, modifies the profile of substrates available for elongation to eicosanoid precursors, and inhibits the elongation of C18 PUFA in this model. The consumption of FO-based products may prove a more practical way of obtaining health benefit than attempts to increase dietary content of unrefined seed.
Assuntos
Gorduras na Dieta/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Linho/química , Óleo de Semente do Linho/farmacologia , Lipoproteínas LDL/metabolismo , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , Animais , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/uso terapêutico , Óleo de Semente do Linho/administração & dosagem , Óleo de Semente do Linho/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Doenças Renais Policísticas/sangue , Doenças Renais Policísticas/tratamento farmacológico , RatosRESUMO
BACKGROUND: Few treatments are available to slow the progression to renal failure in autosomal dominant polycystic kidney disease (PKD). In an animal model of PKD, the male heterozygous Han:SPRD rat, intake of a solution of potassium citrate plus citric acid (KCitr) from age one to three months prevented a decline in glomerular filtration rate (GFR). The present study tested whether this beneficial effect is sustained and explored handling of citrate and ammonia in normal and cystic kidneys. METHODS: Rats were provided with tap water or citrate solutions to drink, and clearance and survival studies were performed. RESULTS: The GFRs of rats with PKD that consumed KCitr from one month of age were normal at six months of age, while those of their counterparts on water were about one third of normal. Long-term KCitr treatment extended the average life span of rats with PKD from 10 to 17 months. Compared with normal rats, water-drinking rats with PKD had higher plasma [citrate], renal cortical [citrate], and fractional excretion of citrate, and lower rates of renal citrate consumption, ammonia synthesis, and ammonia excretion. Cortical PNH3 was not elevated in cystic kidneys. Intake of Na3 citrate/citric acid solution or K3 citrate solution, but not ammonium citrate/citric acid solution, prevented a decline in GFR in three-month-old rats with PKD. CONCLUSIONS: Rats with PKD show abnormal renal handling of citrate and ammonia. Citrate salts that have an alkalinizing effect preserve GFR and extend survival.
Assuntos
Citratos/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Amônia/metabolismo , Animais , Citratos/metabolismo , Ingestão de Líquidos , Eletrólitos/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/fisiopatologia , Citrato de Potássio/uso terapêutico , Ratos , Ratos Mutantes , Soluções , Análise de Sobrevida , ÁguaRESUMO
Woo et al (Nature 368:750-753) reported that parenteral administration of paclitaxel arrested the striking renal enlargement and prolonged life in C57BL/6J-cpk/cpk mice with a rapidly progressive form of polycystic kidney disease (PKD). In the current study, we sought to determine whether paclitaxel could alter the progression of other forms of hereditary PKD in rodents. Paclitaxel was administered by intraperitoneal injection to C57BL/6J-cpk/cpk mice and Han:SPRD-Cy/Cy rats with rapidly progressive PKD and to DBA/2FG-pcy/pcy mice and Han:SPRD-Cy/+ rats with slowly progressive PKD. Paclitaxel (150 micrograms/wk) prolonged the survival of cpk/cpk mice from 24.5 days to more than 65 days and decreased kidney weight relative to body weight from 16.5% at 21 days of age to 8.2% at more than 65 days of age. Mortality attributable to paclitaxel was 12%. By contrast, the administration of paclitaxel (0.1 to 15 mg/kg/wk) to 7- to 10-day-old Han:SPRD-Cy/Cy rats with rapidly progressive PKD had no effect on the course of the disease; moreover, paclitaxel caused severe side effects and premature death in all the Cy/Cy animals. Heterozygous male Cy/+ rats develop slowly progressive renal enlargement and azotemia. Paclitaxel, administered at 7, 15, or 27 mg/kg/wk to male Cy/+ rats from 4 until 10 weeks of age, reduced body weight gain, had an inconsistent effect on kidney weight relative to body weight, and had no effect on the serum urea nitrogen concentration. Mortality associated with the 7, 15, and 27 mg/kg/wk doses of paclitaxel was 0%, 15.4%, and 28.5%, respectively. DBA/2FG-pcy/pcy mice of either sex developed slowly progressive renal enlargement and azotemia. The administration of paclitaxel (100 to 150 micrograms/wk) from 2 to 10 weeks of age to DBA/2FG-pcy/pcy mice with cystic disease had no effect on the increase in kidney weight or on the level of serum urea nitrogen in comparison to untreated cystic animals. Mortality associated with 100- and 150-micrograms/wk doses of paclitaxel was 0% and 20%, respectively. We conclude that paclitaxel diminished the rate of renal enlargement and increased the life span of cpk/cpk mice but not Cy/Cy rats with rapidly progressive forms of PKD. Paclitaxel had no apparent benefit in Cy/+ rats nor pcy/pcy mice with slowly progressive PKD. On the basis of these studies in rodents, it appears that paclitaxel has limited potential usefulness as a therapeutic agent in the treatment of PKD.