RESUMEN
The teleology of sex differences has been argued since at least as early as Aristotle's controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question "why are the sexes different" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question "how are the sexes different" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.
Asunto(s)
Hipertensión , Caracteres Sexuales , Animales , Femenino , Humanos , Masculino , Presión Sanguínea/fisiología , Riñón , Hemodinámica , SodioRESUMEN
Collectrin (Tmem27), an angiotensin-converting enzyme 2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance and increased proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) expression. Collectrin is located on the X chromosome where genome-wide association population studies have largely been excluded. In the present study, we generated PT-specific collectrin KO (PT KO) mice to determine the precise contribution of PT collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single-nucleotide polymorphisms with blood pressure traits in 11,926 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Hispanic/Latino participants. PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity or a reduction in renal blood flow compared with control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific single-nucleotide polymorphism associations with diastolic blood pressure. In conclusion, loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on blood pressure and salt sensitivity in humans.NEW & NOTEWORTHY The findings of our study are significant in several ways: 1) loss of an amino acid chaperone in the proximal tubule is sufficient to cause hypertension, 2) the results in global and proximal tubule-specific collectrin knockout mice support the notion that vascular dysfunction is required for salt sensitivity or that impaired renal tubule function causes hypertension but is not sufficient to cause salt sensitivity, and 3) our study is the first to implicate a role of collectrin in human hypertension.
Asunto(s)
Presión Sanguínea , Hipertensión , Túbulos Renales Proximales , Glicoproteínas de Membrana , Animales , Femenino , Humanos , Masculino , Ratones , Presión Sanguínea/fisiología , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Hipertensión/genética , Túbulos Renales Proximales/metabolismo , Ratones Noqueados , Cloruro de Sodio Dietético/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genéticaRESUMEN
BACKGROUND: GSTM1 encodes glutathione S-transferase µ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation. RESULTS: Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant. CONCLUSIONS: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.
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Brassicaceae , Dieta , Eliminación de Gen , Glutatión Transferasa/genética , Insuficiencia Renal Crónica/genética , Verduras , Animales , Modelos Animales de Enfermedad , Femenino , Glutatión Transferasa/fisiología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Insuficiencia Renal Crónica/prevención & controlRESUMEN
Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.
Asunto(s)
Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Hidronefrosis/prevención & control , Riñón/cirugía , Regeneración , Obstrucción Ureteral/cirugía , Animales , Animales Recién Nacidos , Rastreo Celular/métodos , Modelos Animales de Enfermedad , Fibrosis , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Hidronefrosis/genética , Hidronefrosis/metabolismo , Hidronefrosis/patología , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Ratones Transgénicos , Neovascularización Fisiológica , Estrés Oxidativo , Fenotipo , Circulación Renal , Transducción de Señal , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Obstrucción Ureteral/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.
Asunto(s)
Angiotensina II/fisiología , Regulación hacia Abajo , Hipertensión/etiología , Glicoproteínas de Membrana/fisiología , Cloruro de Sodio Dietético/efectos adversos , Animales , Riñón/metabolismo , Masculino , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones NoqueadosRESUMEN
The plasticity of dendritic cells (DCs) permits phenotypic modulation ex vivo by gene expression or pharmacologic agents, and these modified DCs can exert therapeutic immunosuppressive effects in vivo through direct interactions with T cells, either inducing T regulatory cells (T(REG)s) or causing anergy. Sphingosine 1-phosphate (S1P) is a sphingolipid and the natural ligand for five G protein-coupled receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), and S1PR agonists reduce kidney ischemia-reperfusion injury (IRI) in mice. S1pr3(-/-)mice are protected from kidney IRI, because DCs do not mature. We tested the therapeutic advantage of S1pr3(-/-) bone marrow-derived dendritic cell (BMDC) transfers in kidney IRI. IRI produced a rise in plasma creatinine (PCr) levels in mice receiving no cells (NCs) and mice pretreated with wild-type (WT) BMDCs. However, S1pr3(-/-) BMDC-pretreated mice were protected from kidney IRI. S1pr3(-/-) BMDC-pretreated mice had significantly higher numbers of splenic T(REG)s compared with NC and WT BMDC-pretreated mice. S1pr3(-/-) BMDCs did not attenuate IRI in splenectomized, Rag-1(-/-), or CD11c(+) DC-depleted mice. Additionally, S1pr3(-/-) BMDC-dependent protection required CD169(+)marginal zone macrophages and the macrophage-derived chemokine CCL22 to increase splenic CD4(+)Foxp3(+) T(REG)s. Pretreatment with S1pr3(-/-) BMDCs also induced T(REG)-dependent protection against IRI in an allogeneic mouse model. In summary, adoptively transferred S1pr3(-/-) BMDCs prevent kidney IRI through interactions within the spleen and expansion of splenic CD4(+)Foxp3(+) T(REG)s. We conclude that genetically induced deficiency of S1pr3 in allogenic BMDCs could serve as a therapeutic approach to prevent IRI-induced AKI.
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Células Dendríticas , Riñón/irrigación sanguínea , Receptores de Lisoesfingolípidos/deficiencia , Daño por Reperfusión/fisiopatología , Bazo/fisiopatología , Animales , Trasplante de Médula Ósea , Células Dendríticas/trasplante , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/cirugíaRESUMEN
We showed previously that prior exposure to a modified ultrasound regimen prevents kidney ischemia-reperfusion injury (IRI) likely via the splenic cholinergic anti-inflammatory pathway (CAP) and α7 nicotinic acetylcholine receptors (α7nAChR). However, it is unclear how ultrasound stimulates the splenic CAP. Further investigating the role of the spleen in ischemic injury, we found that prior splenectomy (-7d) or chemical sympathectomy of the spleen with 6-hydroxydopamine (6OHDA; -14d) exacerbated injury after subthreshold (24-minute ischemia) IRI. 6-OHDA-induced splenic denervation also prevented ultrasound-induced protection of kidneys from moderate (26-minute ischemia) IRI. Ultrasound-induced protection required hematopoietic but not parenchymal α7nAChRs, as shown by experiments in bone marrow chimeras generated with wild-type and α7nAChR(-/-) mice. Ultrasound protection was associated with reduced expression of circulating and kidney-derived cytokines. However, splenocytes isolated from mice 24 hours after ultrasound treatment released more IL-6 ex vivo in response to LPS than splenocytes from sham mice. Adoptive transfer of splenocytes from ultrasound-treated (but not sham) mice to naïve mice was sufficient to protect kidneys of recipient mice from IRI. Ultrasound treatment 24 hours before cecal ligation puncture-induced sepsis was effective in reducing plasma creatinine in this model of AKI. Thus, splenocytes of ultrasound-treated mice are capable of modulating IRI in vivo, supporting our ongoing hypothesis that a modified ultrasound regimen has therapeutic potential for AKI and other inflammatory conditions.
Asunto(s)
Lesión Renal Aguda/inmunología , Lesión Renal Aguda/prevención & control , Neuroinmunomodulación/efectos de la radiación , Bazo/inmunología , Bazo/efectos de la radiación , Terapia por Ultrasonido , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Resveratrol has gained popularity as an "anti-aging" compound due to its antioxidant and anti-inflammatory properties. Few studies have investigated the role of resveratrol supplementation in the prevention of age-related bone loss and skeletal disuse despite increased inactivity and age-related bone loss in the elderly. The objective of the study was to investigate the effect of resveratrol supplementation on disuse and age-related bone loss. Old (age 33 months) Fischer 344 × Brown Norway male rats were provided either trans-resveratrol (12.5 mg/kg bw/day) or deionized distilled water by oral gavage for 21 days. Rats were hindlimb-suspended (HLS) or kept ambulatory (AMB) for 14 days. Both femora and tibiae were collected. Bone mass was measured by dual-energy X-ray absorptiometry and bone microstructure was determined by micro-computed tomography. HLS of old male rats accelerated loss of bone mineral content, decreased trabecular bone volume per unit of total volume, and increased trabecular separation. Resveratrol supplementation ameliorated bone demineralization and loss of bone microarchitecture in HLS old male rats. The peak force measured by the three-point bending test was reduced (P = 0.007) in HLS/control compared to AMB/control rats. Resveratrol supplementation ameliorated HLS-induced loss of femur strength. Plasma osteocalcin and alkaline phosphatase was higher (P < 0.04) and C-reactive protein was lower (P = 0.04) in old male rats given resveratrol. The bone protective effects of resveratrol appeared to be mediated through increased osteoblast bone formation, possibly due to reduced inflammation. Based on the results, resveratrol supplementation appeared to provide a feasible dietary therapy for preserving the skeletal system during disuse and age-related bone loss.
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Envejecimiento/fisiología , Huesos/anatomía & histología , Huesos/fisiología , Suplementos Dietéticos , Suspensión Trasera/fisiología , Estilbenos/administración & dosificación , Estilbenos/farmacología , Envejecimiento/efectos de los fármacos , Animales , Biomarcadores/sangre , Fenómenos Biomecánicos/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Femenino , Fémur/anatomía & histología , Fémur/efectos de los fármacos , Fémur/fisiología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Osteocalcina/sangre , Ratas , Resveratrol , Tibia/anatomía & histología , Tibia/efectos de los fármacos , Tibia/fisiología , CaminataRESUMEN
Acute kidney injury (AKI) is an increasing medical burden and is independently associated with mortality. AKI is a common comorbidity in the intensive care unit (ICU), with sepsis-associated AKI seen in almost a quarter of all ICU patients. Due to the high mortality seen in these patients, improved therapeutic options are needed. Data from experimental studies in animals support observations in humans that the host immune response to sepsis and trauma contributes to multiorgan failure and the high morbidity and mortality seen in critically ill patients. The spleen, a major component of the reticuloendothelial system, appears to be a key player in the 'cytokine storm' that develops after infection and trauma, and the resultant systemic inflammation is regulated by the autonomic nervous system. Over the past decade, evidence has suggested that controlling the splenic cytokine response improves tissue function and mortality in sepsis and other inflammatory-mediated diseases. One pathway that controls the response of the spleen to sepsis and trauma is the cholinergic anti-inflammatory pathway, and it may provide a key target for therapeutic intervention. Here, we review this concept and highlight the potential use of ultrasound to stimulate the cholinergic anti-inflammatory pathway and reduce systemic inflammation and disease severity.
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Lesión Renal Aguda/inmunología , Enfermedad Crítica , Bazo/inmunología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/terapia , Traslado Adoptivo , Animales , Sistema Nervioso Autónomo/inmunología , Sistema Nervioso Autónomo/fisiopatología , Linfocitos T CD4-Positivos/inmunología , Fibras Colinérgicas/diagnóstico por imagen , Fibras Colinérgicas/fisiología , Cuidados Críticos , Citocinas/fisiología , Humanos , Inflamación , Sistema Mononuclear Fagocítico/inmunología , Sistema Mononuclear Fagocítico/fisiopatología , Neuroinmunomodulación/fisiología , Norepinefrina/metabolismo , Fagocitos/inmunología , Receptores Adrenérgicos/fisiología , Sepsis/complicaciones , Sepsis/inmunología , Bazo/fisiopatología , Esplenectomía , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Factor de Necrosis Tumoral alfa/fisiología , Terapia por Ultrasonido , UltrasonografíaRESUMEN
AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b(+)Ly6G(high) neutrophils and CD11b(+)F4/80(high) myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4(+) T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic anti-inflammatory pathway.
Asunto(s)
Riñón/irrigación sanguínea , Riñón/patología , Receptores Colinérgicos/fisiología , Daño por Reperfusión/prevención & control , Transducción de Señal/fisiología , Bazo/fisiología , Terapia por Ultrasonido , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Antígeno CD11b/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/fisiología , Modelos Animales de Enfermedad , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/inmunología , Células Mieloides/patología , Neutrófilos/inmunología , Neutrófilos/patología , Receptores Colinérgicos/deficiencia , Receptores Colinérgicos/genética , Receptores Nicotínicos/deficiencia , Receptores Nicotínicos/genética , Receptores Nicotínicos/fisiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Bazo/cirugía , Esplenectomía , Receptor Nicotínico de Acetilcolina alfa 7Asunto(s)
Haploinsuficiencia , Hipertensión , Animales , Riñón , Ratas , Ratas Endogámicas Dahl , Cloruro de Sodio Dietético , Factores de TranscripciónRESUMEN
BACKGROUND: Cardiovascular disease has had an unquestioned status of the number one cause of death in the US since 1921. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have cardio-protective benefits. However, egg is typically a poor source of ω-3 PUFAs and, in general, the American diet is low in these cardio-protective fatty acids. Novel, nutritionally enhanced egg products were developed by substituting yolk with ω-3 PUFA-rich flaxseed, menhaden, algae, or krill oil. Experimental egg products matched composition of hen egg (whole egg). The experimental egg products, mixed whole egg, and a liquid egg product (Egg Beaters) were microwave-cooked and compared. RESULTS: Although fat, protein, and moisture contents of experimental egg products matched (P > 0.05) mixed whole egg, experimental egg products had more (P < 0.05) ω-3 PUFAs, lower (P < 0.05) ω-6/ω-3 ratio, and depending on oil added, a higher (P < 0.05) unsaturated/saturated fatty acids ratio compared to mixed whole egg. Triglycerides were the main lipid class in all experimental egg products except those developed with krill oil, which had even more phospholipids than mixed whole egg. Analysis of thiobarbituric acid reactive substances showed that lipid oxidation of experimental egg products was lower (P < 0.05) or similar (P > 0.05) to mixed whole egg, except for experimental egg products with krill oil. However, peroxide value showed that all egg samples had minimal oxidation. Experimental egg products developed with menhaden or flaxseed oil had the highest (P < 0.05) concentration of the antioxidant, ethyoxquin compared to all other egg samples. However, experimental egg products with krill oil likely contained a natural antioxidant, astaxanthin. CONCLUSION: This study demonstrated an alternative approach to developing novel, nutraceutical egg products. Instead of dietary modification of chicken feed, yolk substitution with ω-3 PUFAs oils resulted in enhancement of ω-3 PUFAs beyond levels possible to achieve by modifying chicken feed.
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Antioxidantes/análisis , Huevos/análisis , Ácidos Grasos Omega-3/metabolismo , Alimentos Fortificados , Peroxidación de Lípido , Lípidos/análisis , Aceites/química , Animales , Enfermedades Cardiovasculares/prevención & control , Culinaria , Suplementos Dietéticos , Yema de Huevo , Euphausiacea , Aceites de Pescado , Lino , Tecnología de Alimentos , Humanos , Microondas , Oxidación-Reducción , Peróxidos/análisis , Estramenopilos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Female Sprague-Dawley rats provide an animal model for studying the role of nutrition in renal health due to their sensitivity to diet-induced alterations in kidney function. Nephrocalcinosis, a common renal abnormality found in rats, has been implicated in subsequent renal failure. Simple dietary manipulations, such as changing the source of dietary protein, may influence nephrocalcinosis. This study evaluates the consumption of krill protein concentrate (KPC), a novel and high-quality protein, on renal and bone health. Young female Sprague-Dawley rats (n = 10/group) were individually housed in metabolic cages and fed ad libitum diets consisting of 10% crude protein supplied as KPC or casein for 4 weeks. Diets were isocaloric, isonitrogenous, and matched for calcium (Ca) and phosphorus (P). Urinary n-acetyl glucosaminidase (NAG) was measured and kidney histology performed to assess kidney damage. Biomarkers of kidney function were determined by calorimetric assays. Ca and P balance and bone concentrations were measured using inductively coupled plasma mass spectrometry. Femoral strength was determined by three-point bend testing. Rats fed KPC had lower (P = 0.005) urinary NAG levels and minimal microtubular Ca deposition compared to rats fed casein. There was a tendency (P < 0.06) for higher glomerular filtration rates and lower proteinuria, and higher (P = 0.03) urinary output in rats fed KPC compared to casein. There were no differences in Ca and P balance or bone measurements of total bone mineral content, Ca, P or strength between rats fed KPC and casein. Based on the study results, KPC prevented early renal injury leading to nephrocalcinosis and potential bone loss.
Asunto(s)
Proteínas en la Dieta/farmacología , Riñón/metabolismo , Nefrocalcinosis/dietoterapia , Animales , Huesos/química , Huesos/metabolismo , Calcio/análisis , Calcio/metabolismo , Calcio de la Dieta/análisis , Calcio de la Dieta/metabolismo , Caseínas/análisis , Caseínas/metabolismo , Crustáceos , Euphausiacea/metabolismo , Femenino , Riñón/química , Riñón/patología , Nefrocalcinosis/metabolismo , Nefrocalcinosis/patología , Fósforo/análisis , Fósforo/metabolismo , Fósforo Dietético/análisis , Fósforo Dietético/metabolismo , Proteinuria/metabolismo , Proteinuria/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Numerous health benefits associated with increased omega-3 polyunsaturated fatty acid (n-3 PUFA) consumption has lead to an increasing variety of available n-3 PUFA sources. However, sources differ in the type, amount, and structural form of the n-3 PUFAs. Therefore, the objective of this study was to determine the effect of different sources of ω-3 PUFAs on digestibility, tissue deposition, eicosanoid metabolism, and oxidative stability. METHODS: Female Sprague-Dawley rats (age 28 d) were randomly assigned (n = 10/group) to be fed a high fat 12% (wt) diet consisting of either corn oil (CO) or n-3 PUFA rich flaxseed (FO), krill (KO), menhaden (MO), salmon (SO) or tuna (TO) oil for 8 weeks. Rats were individually housed in metabolic cages to determine fatty acid digestibility. Diet and tissue fatty acid composition was analyzed by gas chromatography and lipid classes using thin layer chromatography. Eicosanoid metabolism was determined by measuring urinary metabolites of 2-series prostaglandins (PGs) and thromoboxanes (TXBs) using enzyme immunoassays. Oxidative stability was assessed by measuring thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) using colorimetric assays. Gene expression of antioxidant defense enzymes was determined by real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Rats fed KO had significantly lower DHA digestibility and brain DHA incorporation than SO and TO-fed rats. Of the n-3 PUFA sources, rats fed SO and TO had the highest n-3 PUFAs digestibility and in turn, tissue accretion. Higher tissue n-3 LC-PUFAs had no significant effect on 2-series PG and TXB metabolites. Despite higher tissue n-3 LC-PUFA deposition, there was no increase in oxidation susceptibility indicated by no significant increase in TBARS or decrease in TAC and gene expression of antioxidant defense enzymes, in SO or TO-fed rats. CONCLUSIONS: On the basis that the optimal n-3 PUFA sources should provide high digestibility and efficient tissue incorporation with the least tissue lipid peroxidation, TO and SO appeared to be the most beneficial of the n-3 PUFAs sources evaluated in this study.
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Digestión , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/metabolismo , Peroxidación de Lípido , Aceites/metabolismo , Tejido Adiposo Blanco/crecimiento & desarrollo , Tejido Adiposo Blanco/metabolismo , Animales , Peso Corporal , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Eicosanoides/metabolismo , Eicosanoides/orina , Euphausiacea/química , Femenino , Aceites de Pescado/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hígado/enzimología , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Tamaño de los Órganos , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Aceites de Plantas/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available "Western" diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.
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Dieta Occidental , Dieta , Ácido Fólico/toxicidad , Enfermedades Renales/prevención & control , Daño por Reperfusión/prevención & control , Animales , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/patología , Factores de RiesgoRESUMEN
OBJECTIVE: Acute hyperglycemia during myocardial infarction worsens outcomes in part by inflammatory mechanisms. Pulsed ultrasound has anti-inflammatory potential in bone healing and neuromodulation. We hypothesized that pulsed ultrasound would attenuate the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury via the cholinergic anti-inflammatory pathway. METHODS: Acute hyperglycemia was induced in wild-type C57BL6 or acetylcholine-receptor knockout (α7nAChR-/-) mice by intraperitoneal injection of glucose. Pulsed ultrasound (frequency 7 MHz, bursting mechanical index 1.2, duration 1 second, repeated every 6 seconds for 2 minutes, 20-second total exposure) was performed at the spleen or neck after glucose injection. Separate mice underwent vagotomy before treatment. The left coronary artery was occluded for 20 minutes, followed by 60 minutes of reperfusion. The primary end point was infarct size in explanted hearts. RESULTS: Splenic pulsed ultrasound significantly decreased infarct size in wild-type C57BL6 mice exposed to acute hyperglycemia and myocardial ischemia-reperfusion injury (5.2% ± 4.4% vs 16.9% ± 12.5% of risk region, P = .013). Knockout of α7nAChR abrogated the beneficial effect of splenic pulsed ultrasound (22.2% ± 12.1%, P = .79 vs control). Neck pulsed ultrasound attenuated the hyperglycemic exacerbation of myocardial infarct size (3.5% ± 4.8%, P = .004 vs control); however, the cardioprotective effect disappeared in mice that underwent vagotomy. Plasma acetylcholine, ß2 adrenergic receptor, and phosphorylated Akt levels were increased after splenic pulsed ultrasound treatment. CONCLUSIONS: Pulsed ultrasound treatment of the spleen or neck attenuated the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury leading to a 3-fold decrease in infarct size. Pulsed ultrasound may provide cardioprotection via the cholinergic anti-inflammatory pathway and could be a promising new nonpharmacologic, noninvasive therapy to reduce infarct size during acute myocardial infarction and improve patient outcomes.
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Hiperglucemia/complicaciones , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/prevención & control , Terapia por Ultrasonido , Acetilcolina/metabolismo , Animales , Modelos Animales de Enfermedad , Hiperglucemia/metabolismo , Hiperglucemia/patología , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/metabolismo , Receptores Colinérgicos/metabolismo , Transducción de Señal , Bazo , Ondas UltrasónicasRESUMEN
Apple processing results in peel, stem, seeds, and pulp being left as a waste product known as apple pomace. This review comprehensively assessed apple pomace composition for nutritional value and bioactive substances and evaluated potential health benefits and safety. Apple pomace is a rich source of health-benefitting nutrients, including minerals, dietary fiber, antioxidants, and ursolic acid, which suggests it has potential use as a dietary supplement, functional food, and/or food additive. Preclinical studies have found apple pomace and its isolated extracts improved lipid metabolism, antioxidant status, and gastrointestinal function and had a positive effect on metabolic disorders (eg, hyperglycemia, insulin resistance, etc.). Safety studies have shown apple pomace to be a safe livestock feed additive and to have pesticide concentrations within safety thresholds established for human consumption. Commercial development of apple pomace for human consumption requires more research focusing on standardized methods of nutrient reporting, mechanistic studies, and human clinical trials.
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Antioxidantes/farmacología , Fibras de la Dieta/farmacología , Suplementos Dietéticos , Frutas/química , Malus/química , Minerales/farmacología , Triterpenos/farmacología , Antioxidantes/análisis , Antioxidantes/metabolismo , Fibras de la Dieta/análisis , Digestión/efectos de los fármacos , Industria de Alimentos , Alimentos Funcionales , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedades Metabólicas/tratamiento farmacológico , Minerales/análisis , Valor Nutritivo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Semillas/química , Triterpenos/análisis , Ácido UrsólicoRESUMEN
Polycystic kidney disease (PKD) is a heritable disease characterized by renal cysts and is a leading cause of end-stage renal disease. Dietary intervention offers a potentially efficacious, cost-effective, and safe therapeutic option for PKD. The aim of this article was to review studies investigating the effect of dietary components on PKD and potential mechanisms of action. Low-protein diets are commonly recommended for PKD patients, but inconsistent findings in human and animal PKD studies suggest that the type rather the amount of protein may be of greater importance. Dietary soy protein has been shown to have renal protective effects in various animal models of PKD. Other than dietary proteins, studies investigating the role of the amount and type of dietary lipids on PKD progression are increasing. The omega-3 polyunsaturated fatty acids can alter multiple steps in PKD pathogenesis. Phytoestrogens and phytochemicals are other dietary compounds shown to attenuate cyst pathogenesis in animal studies. A better understanding of the role of nutrition in PKD can contribute to the development of dietary recommendations and diet-based therapies to reduce PKD progression and severity.
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Dieta con Restricción de Proteínas , Enfermedades Renales Poliquísticas/dietoterapia , Animales , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/farmacología , Progresión de la Enfermedad , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/farmacología , Humanos , Isoflavonas/administración & dosificación , Isoflavonas/farmacología , Fitoquímicos/administración & dosificación , Fitoquímicos/farmacología , Enfermedades Renales Poliquísticas/metabolismo , Enfermedades Renales Poliquísticas/patología , Índice de Severidad de la Enfermedad , Proteínas de Soja/administración & dosificación , Proteínas de Soja/farmacologíaRESUMEN
The deleterious bone effects of mechanical unloading have been suggested to be due to oxidative stress and (or) inflammation. Resveratrol has both antioxidant and anti-inflammatory properties; therefore, the study's objective was to determine whether providing resveratrol in the low supplementation range for a short duration prevents bone loss during mechanical unloading. Mature (6 months old) Fischer 344 × Brown Norway male rats were hindlimb-suspended (HLS) or kept ambulatory for 14 days. Rats were provided either trans-resveratrol (RES; 12.5 mg/kg body mass per day) or deionized distilled water by oral gavage for 21 days (7 days prior to and during the 14 days of HLS). Bone mass was measured by dual energy X-ray absorptiometry. Bone microstructure was determined by microcomputed tomography. HLS of rats resulted in femur trabecular bone deterioration. Resveratrol supplementation did not attenuate trabecular bone deterioration in HLS rats. Unexpectedly, HLS-RES rats had the lowest tibial bone mineral content (P < 0.05), calcium content and lower cortical thickness (P < 0.05), and increased porosity compared with HLS/control rats. Plasma osteocalcin was also lower (P < 0.04) in HLS/resveratrol rats. There were no significant effects on plasma C-reactive protein, a marker of systemic inflammation, or total antioxidant capacity. However, HLS-RES rats showed a negative relationship (r(2) = 0.69, P = 0.02) between plasma osteocalcin and thiobarbituric acid reactive substances, a marker of lipid peroxidation. Based on the results, resveratrol supplementation of 6-month-old HLS male rats had no bone protective effects and possibly even detrimental bone effects.
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Huesos/efectos de los fármacos , Huesos/fisiología , Suspensión Trasera , Estilbenos/administración & dosificación , Absorciometría de Fotón , Animales , Fenómenos Biomecánicos , Densidad Ósea , Enfermedades Óseas Metabólicas/patología , Enfermedades Óseas Metabólicas/fisiopatología , Enfermedades Óseas Metabólicas/prevención & control , Huesos/patología , Calcio/análisis , Suplementos Dietéticos , Miembro Posterior , Masculino , Osteocalcina/sangre , Osteoporosis/prevención & control , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Resveratrol , Estilbenos/efectos adversos , TibiaRESUMEN
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) consumption has been reported to improve bone health. However, sources of ω-3 PUFAs differ in the type of fatty acids and structural form. The study objective was to determine the effect of various ω-3 PUFAs sources on bone during growth. Young (age 28d) female Sprague-Dawley rats were randomly assigned (n=10/group) to a high fat 12% (wt) diet consisting of either corn oil (CO) or ω-3 PUFA rich, flaxseed (FO), krill (KO), menhaden (MO), salmon (SO) or tuna (TO) for 8 weeks. Bone mass was assessed by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture by micro-computed tomography (µCT). Bone turnover markers were measured by enzyme immunoassay. Lipid peroxidation was measured by calorimetric assays. Results showed that rats fed TO, rich in docosahexaenoic acid (DHA, 22:6ω-3) had higher (P<0.009) tibial bone mineral density (BMD) and bone mineral content (BMC) and lower (P=0.05) lipid peroxidation compared to the CO-fed rats. Reduced lipid peroxidation was associated with increased tibial BMD (r2=0.08, P=0.02) and BMC (r2=0.71, P=0.01). On the other hand, rats fed FO or MO, rich in alpha-linolenic acid (ALA, 18:3ω-3), improved bone microarchitecture compared to rats fed CO or SO. Serum osteocalcin was higher (P=0.03) in rats fed FO compared to rats fed SO. Serum osteocalcin was associated with improved trabecular bone microarchitecture. The animal study results suggest consuming a variety of ω-3 PUFA sources to promote bone health during the growth stage.