RESUMEN
An intrinsic cellular circadian clock is located in nearly every cell of the body. The peripheral circadian clocks within the cells of the kidney contribute to the regulation of a variety of renal processes. In this review, we summarize what is currently known regarding the function, mechanism, and regulation of kidney clocks. Additionally, the effect of extrarenal physiological processes, such as endocrine and neuronal signals, on kidney function is also reviewed. Circadian rhythms in renal function are an integral part of kidney physiology, underscoring the importance of considering time of day as a key biological variable. The field of circadian renal physiology is of tremendous relevance, but with limited physiological and mechanistic information on the kidney clocks this is an area in need of extensive investigation.
Asunto(s)
Relojes Circadianos , Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Sistema Endocrino , Humanos , Riñón/fisiologíaRESUMEN
The circadian clock protein basic helix-loop-helix aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a transcription factor that impacts kidney function, including blood pressure (BP) control. Previously, we have shown that male, but not female, kidney-specific cadherin Cre-positive BMAL1 knockout (KS-BMAL1 KO) mice exhibit lower BP compared with littermate controls. The goal of this study was to determine the BP phenotype and immune response in male KS-BMAL1 KO mice in response to a low-K+ high-salt (LKHS) diet. BP, renal inflammatory markers, and immune cells were measured in male mice following an LKHS diet. Male KS-BMAL1 KO mice had lower BP following the LKHS diet compared with control mice, yet their circadian rhythm in pressure remained unchanged. Additionally, KS-BMAL1 KO mice exhibited lower levels of renal proinflammatory cytokines and immune cells following the LKHS diet compared with control mice. KS-BMAL1 KO mice were protected from the salt-sensitive hypertension observed in control mice and displayed an attenuated immune response following the LKHS diet. These data suggest that BMAL1 plays a role in driving the BP increase and proinflammatory environment that occurs in response to an LKHS diet.NEW & NOTEWORTHY We show here, for the first time, that kidney-specific BMAL1 knockout mice are protected from blood pressure (BP) increases and immune responses to a salt-sensitive diet. Other kidney-specific BMAL1 knockout models exhibit lower BP phenotypes under basal conditions. A salt-sensitive diet exacerbates this genotype-specific BP response, leading to fewer proinflammatory cytokines and immune cells in knockout mice. These data demonstrate the importance of distal segment BMAL1 in BP and immune responses to a salt-sensitive environment.
Asunto(s)
Factores de Transcripción ARNTL , Hipertensión , Animales , Masculino , Ratones , Factores de Transcripción ARNTL/metabolismo , Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Citocinas , Dieta , Hipertensión/genética , Hipertensión/prevención & control , Riñón/metabolismo , Ratones Noqueados , Cloruro de Sodio DietéticoRESUMEN
Endothelin-1 (ET-1) is a peptide hormone that acts on its receptors to regulate sodium handling in the kidney's collecting duct. Dysregulation of the endothelin axis is associated with various diseases, including salt-sensitive hypertension and chronic kidney disease. Previously, our lab has shown that the circadian clock gene PER1 regulates ET-1 levels in mice. However, the regulation of ET-1 by PER1 has never been investigated in rats. Therefore, we used a novel model where knockout of Per1 was performed in Dahl salt-sensitive rat background (SS Per1 -/-) to test a hypothesis that PER1 regulates the ET-1 axis in this model. Here, we show increased renal ET-1 peptide levels and altered endothelin axis gene expression in several tissues, including the kidney, adrenal glands, and liver in SS Per1 -/- compared with control SS rats. Edn1 antisense lncRNA Edn1-AS, which has previously been suggested to be regulated by PER1, was also altered in SS Per1 -/- rats compared with control SS rats. These data further support the hypothesis that PER1 is a negative regulator of Edn1 and is important in the regulation of the endothelin axis in a tissue-specific manner.
Asunto(s)
Relojes Circadianos , Hipertensión , Ratas , Ratones , Animales , Ratas Endogámicas Dahl , Relojes Circadianos/genética , Endotelinas , Riñón/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Factores de Transcripción/metabolismo , Presión Sanguínea/fisiología , Proteínas Circadianas Period/genéticaRESUMEN
PERIOD 1 (PER1) is a circadian clock transcription factor that is regulated by aldosterone, a hormone that increases blood volume and Na+ retention to increase blood pressure. Male global Per1 knockout (KO) mice develop reduced night/day differences in Na+ excretion in response to a high-salt diet plus desoxycorticosterone pivalate treatment (HS + DOCP), a model of salt-sensitive hypertension. In addition, global Per1 KO mice exhibit higher aldosterone levels on a normal-salt diet. To determine the role of Per1 in the kidney, male kidney-specific Per1 KO (KS-Per1 KO) mice were generated using Ksp-cadherin Cre recombinase to remove exons 2-8 of Per1 in the distal nephron and collecting duct. Male KS-Per1 KO mice have increased Na+ retention but have normal diurnal differences in Na+ excretion in response to HS + DOCP. The increased Na+ retention is associated with altered expression of glucocorticoid and mineralocorticoid receptors, increased serum aldosterone, and increased medullary endothelin-1 compared with control mice. Adrenal gland gene expression analysis revealed that circadian clock and aldosterone synthesis genes have altered expression in KS-Per1 KO mice compared with control mice. These results emphasize the importance of the circadian clock not only in maintaining rhythms of physiological functions but also for adaptability in response to environmental cues, such as HS + DOCP, to maintain overall homeostasis. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis.NEW & NOTEWORTHY For the first time, we show that knockout of the circadian clock transcription factor PERIOD 1 using kidney-specific cadherin Cre results in increased renal Na+ reabsorption, increased aldosterone levels, and changes in gene expression in both the kidney and adrenal gland. Diurnal changes in renal Na+ excretion were not observed, demonstrating that the clock protein PER1 in the kidney is important for maintaining homeostasis and that this effect may be independent of time of day.
Asunto(s)
Aldosterona , Relojes Circadianos , Hipertensión , Riñón , Proteínas Circadianas Period , Aldosterona/sangre , Animales , Cadherinas/metabolismo , Relojes Circadianos/genética , Expresión Génica , Riñón/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Sodio/metabolismo , Cloruro de Sodio Dietético/metabolismoRESUMEN
Nontraditional work schedules, such as shift work, have been associated with numerous health issues, including cardiovascular and metabolic disease. These work schedules can chronically misalign environmental timing cues with internal circadian clock systems in the brain and in peripheral organs, leading to dysfunction of those systems and their associated biological processes. Environmental circadian disruption in the kidney may be an important factor in the increased incidence of hypertension and adverse health outcomes in human shift workers. The relationship between renal rhythmicity and injury resilience is not well understood, especially in the context of environmental, rather than genetic, manipulations of the circadian system. We conducted a longitudinal study to determine whether chronic shifting of the light cycle that mimics shift work schedules would disrupt output rhythms of the kidney and accelerate kidney injury in salt-loaded male spontaneously hypertensive, stroke-prone rats. We observed that chronic shifting of the light-dark (LD) cycle misaligned and decreased the amplitude of urinary volume rhythms as the kidney phase-shifted to match each new lighting cycle. This schedule also accelerated glomerular and tubular injury marker excretion, as quantified by nephrin and KIM-1 compared with rats kept in a static LD cycle. These data suggest that disrupted rhythms in the kidney may decrease resilience and contribute to disease development in systems dependent on renal and cardiovascular functions.
Asunto(s)
Ritmo Circadiano , Riñón/metabolismo , Riñón/fisiología , Fotoperiodo , Animales , Biomarcadores , Masculino , Ratas , Ratas Endogámicas SHR , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/toxicidad , UrinálisisRESUMEN
Noninvasive determination of the severity of parenchymal injury in acute kidney injury remains challenging. Edema is an early pathological process following injury, which may correlate with changes in kidney volume. The goal of the present study was to test the hypothesis that "increases in kidney volume measured in vivo using ultrasound correlate with the degree of renal parenchymal injury." Ischemia-reperfusion (IR) of varying length was used to produce graded tissue injury. We first determined 1) whether regional kidney volume in rats varied with the severity (0, 15, 30, and 45 min) of warm bilateral IR and 2) whether this correlated with tubular injury score. We then determined whether these changes could be measured in vivo using three-dimensional ultrasound. Finally, we evaluated cumulative changes in kidney volume up to 14 days post-IR in rats to determine whether changes in renal volume were predictive of latent tubular injury following recovery of filtration. Experiments concluded that noninvasive ultrasound measurements of change in kidney volume over 2 wk are predictive of tubular injury following IR even in animals in which plasma creatinine was not elevated. We conclude that ultrasound measurements of volume are a sensitive, noninvasive marker of tissue injury in rats and that the use of three-dimensional ultrasound measurements may provide useful information regarding the timing, severity, and recovery from renal tissue injury in experimental studies.
Asunto(s)
Lesión Renal Aguda/diagnóstico por imagen , Lesión Renal Aguda/patología , Riñón/patología , Daño por Reperfusión/patología , Ultrasonografía , Animales , Femenino , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Sprague-DawleyRESUMEN
The renal circadian clock has a major influence on the function of the kidney. Aryl hydrocarbon receptor nuclear translocator-like protein 1 [ARNTL; also known as brain and muscle ARNT-like 1 (BMAL1)] is a core clock protein and transcription factor that regulates the expression of nearly half of all genes. Using male and female kidney-specific cadherin BMAL1 knockout (KS-BMAL1 KO) mice, we examined the role of renal distal segment BMAL1 in blood pressure control and solute handling. We confirmed that this mouse model does not express BMAL1 in thick ascending limb, distal convoluted tubule, and collecting duct cells, which are the final locations for solute and fluid regulation. Male KS-BMAL1 KO mice displayed a substantially lower basal systolic blood pressure compared with littermate control mice, yet their circadian rhythm in pressure remained unchanged [male control mice: 127 ± 0.7 mmHg (n = 4) vs. male KS-BMAL KO mice: 119 ± 2.3 mmHg (n = 5), P < 0.05]. Female mice, however, did not display a genotype difference in basal systolic blood pressure [female control mice: 120 ± 1.6 mmHg (n = 5) vs. female KS-BMAL1 KO mice: 119 ± 1.5 mmHg (n = 7), P = 0.4]. In addition, male KS-BMAL1 KO mice had less Na+ retention compared with control mice in response to a K+-restricted diet (15% less following 5 days of treatment). However, there was no genotype difference in Na+ handling after a K+-restricted diet in female mice. Furthermore, there was evidence indicating a sex-specific response to K+ restriction where female mice reabsorbed less Na+ in response to this dietary challenge compared with male mice. We propose that BMAL1 in the distal nephron and collecting duct contributes to blood pressure regulation and Na+ handling in a sex-specific manner.
Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Presión Sanguínea , Ritmo Circadiano , Nefronas/metabolismo , Reabsorción Renal , Sodio/metabolismo , Factores de Transcripción ARNTL/deficiencia , Factores de Transcripción ARNTL/genética , Animales , Femenino , Genotipo , Homeostasis , Túbulos Renales Colectores/metabolismo , Masculino , Ratones Noqueados , Fenotipo , Potasio en la Dieta/metabolismo , Factores Sexuales , Factores de TiempoRESUMEN
Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we have shown that the endothelin-1 (ET-1) gene is targeted by both PER1 and aldosterone. We hypothesized that ET-1 would exhibit a sex-specific response to HS/DOCP treatment in PER1 KO. Here we show that male, but not female, global PER1 KO mice exhibit a decreased night/day ratio of urinary ET-1. Gene expression analysis revealed significant genotype differences in ET-1 and endothelin A receptor (ETA) expression in male, but not female, mice in response to HS/DOCP. Additionally, both wild-type and global PER1 KO male mice significantly increase endothelin B receptor (ETB) expression in response to HS/DOCP, but female mice do not. Finally, siRNA-mediated knockdown of PER1 in mouse cortical collecting duct cells (mpkCCDc14) resulted in increased ET-1 mRNA expression and peptide secretion in response to aldosterone treatment. These data suggest that PER1 is a negative regulator of ET-1 expression in response to HS/DOCP, revealing a novel mechanism for the regulation of renal Na handling in response to HS/DOCP treatment.
Asunto(s)
Endotelina-1/metabolismo , Hipertensión/metabolismo , Túbulos Renales Colectores/fisiopatología , Proteínas Circadianas Period/metabolismo , Eliminación Renal/fisiología , Aldosterona/administración & dosificación , Aldosterona/efectos adversos , Animales , Relojes Circadianos/fisiología , Modelos Animales de Enfermedad , Endotelina-1/orina , Femenino , Humanos , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Túbulos Renales Colectores/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Proteínas Circadianas Period/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Eliminación Renal/efectos de los fármacos , Factores Sexuales , Cloruro de Sodio Dietético/efectos adversos , Cloruro de Sodio Dietético/metabolismoRESUMEN
A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.
Asunto(s)
Apoptosis , Proliferación Celular , Galectina 3/biosíntesis , Regulación de la Expresión Génica , Hipertensión Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fibrosis Pulmonar/metabolismo , Animales , Proteínas Sanguíneas , Modelos Animales de Enfermedad , Galectina 3/genética , Galectinas , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Masculino , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Ratas , Ratas Sprague-DawleyRESUMEN
The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs, including blood pressure. Our laboratory has previously demonstrated the importance of the clock protein period 1 (PER1) in blood pressure regulation in male mice. Briefly, a high-salt diet (HS; 4% NaCl) plus injection with the long-acting mineralocorticoid deoxycorticosterone pivalate (DOCP) resulted in nondipping hypertension [<10% difference between night and day blood pressure (BP) in Per1-knockout (KO) mice but not in wild-type (WT) mice]. To date, there have been no studies that have examined the effect of a core circadian gene KO on BP rhythms in female mice. The goal of the present study was to determine whether female Per1-KO mice develop nondipping hypertension in response to HS/DOCP treatment. For the first time, we demonstrate that loss of the circadian clock protein PER1 in female mice does not significantly change mean arterial pressure (MAP) or the BP rhythm relative to female C57BL/6 WT control mice. Both WT and Per1-KO female mice experienced a significant increase in MAP in response to HS/DOCP. Importantly, however, both genotypes maintained a >10% dip in BP on HS/DOCP. This effect is distinct from the nondipping hypertension seen in male Per1-KO mice, demonstrating that the female sex appears to be protective against PER1-mediated nondipping hypertension in response to HS/DOCP. Together, these data suggest that PER1 acts in a sex-dependent manner in the regulation of cardiovascular rhythms.
Asunto(s)
Relojes Circadianos/genética , Ritmo Circadiano/genética , Hipertensión/genética , Proteínas Circadianas Period/deficiencia , Animales , Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Femenino , Hipertensión/fisiopatología , Ratones Endogámicos C57BL , Mineralocorticoides , Proteínas Circadianas Period/genética , Cloruro de Sodio Dietético/metabolismoRESUMEN
Female spontaneously hypertensive rats (SHR) have more renal regulatory T cells (Tregs) than males, and greater levels of Tregs in female SHR are dependent on blood pressure (BP). However, the molecular mechanism responsible for greater Tregs in female SHR is unknown. Transforming growth factor (TGF)-ß is a pleiotropic cytokine critical in the differentiation of naïve T cells into Tregs, and female SHR have higher TGF-ß excretion than male SHR. The goals of the current study were to test the hypotheses that 1) female SHR have greater renal TGF-ß expression than male SHR, which is dependent on BP and 2) neutralizing TGF-ß will decrease renal Tregs in female SHR. Renal cortices were isolated from 5- and 13-wk-old male and female SHR, and TGF-ß levels were measured via Western blot and ELISA. Adult female SHR have more free, active TGF-ß1 than 5-wk-old female SHR (46% more) or male SHR (44% more than 5-wk-old males and 56% more than 13-wk-old male SHR). We confirmed greater TGF-ß1 in adult female SHR was due to increases in BP and not sexual maturation by measuring TGF-ß1 levels following treatment with BP-lowering drugs or ovariectomy. Separate female SHR were treated with an antibody to TGF-ß1,2,3; BP was measured, and T cells were assessed in whole blood and the kidney. Neutralizing TGF-ß had no effect on BP, although circulating Tregs decreased by 32%, while Th17 cells increased by 64%. Renal Tregs were not altered by antibody treatment, although Th17 cells were decreased by 61%. In conclusion, although TGF-ß promotes circulating Tregs in female SHR, it does not account for the sex difference in renal Tregs in SHR.
Asunto(s)
Hipertensión/inmunología , Riñón/inmunología , Caracteres Sexuales , Linfocitos T Reguladores , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antihipertensivos/uso terapéutico , Femenino , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Riñón/metabolismo , Masculino , Ratas Endogámicas SHRRESUMEN
Recent evidence suggests that a greater density of pericytes in renal cadaveric allografts is associated with better recovery following transplant. The physiological mechanism(s) through which pericyte density may be beneficial is not well understood. The goal of this study was to test the hypothesis that lower medullary pericyte density is associated with greater renal injury following ischemia reperfusion (IR) in a rat model, providing a basis for future studies to better understand pericytes in a pathological environment. To test our hypothesis, we determined the association between medullary pericyte density and renal injury in spontaneously hypertensive rats (SHR) following 45 min of warm bilateral IR. We found that there was a significant negative relationship between pericyte density and plasma creatinine (slope = -0.03, P = 0.02) and blood urea nitrogen (slope = -0.5, P = 0.01) in female but not male SHR. Pericyte density was negatively associated with medullary peritubular capillary (PT) congestion in both sexes following IR (male: slope = -0.04, P = 0.009; female: slope = -0.03, P = 0.0001). To further test this relationship, we used a previously reported method to reduce pericyte density in SHR. Medullary erythrocyte congestion in vasa recta (VR) and PT significantly increased following IR in both sexes when pericyte density was pharmacologically decreased (VR: P = 0.03; PT: P = 0.03). Our data support the hypothesis that pericyte density is negatively associated with the development of IR injury in SHR, which may be mediated by erythrocyte congestion in the medullary vasculature.
Asunto(s)
Médula Renal/irrigación sanguínea , Pericitos/fisiología , Daño por Reperfusión/fisiopatología , Animales , Capilares/fisiopatología , Femenino , Riñón/irrigación sanguínea , Masculino , Ratas , Ratas Endogámicas SHR , Circulación Renal/fisiologíaRESUMEN
Hypertension affects one-third of adults in the Western world and is the most common independent risk factor for cardiovascular disease, and the leading cause of premature death globally. Despite available therapeutic options, approximately half of the hypertensive population taking medication does not achieve adequate blood pressure (BP) control leaving them at increased risk of chronic kidney disease, renal failure, stroke, congestive heart failure, myocardial infarction, aneurysm and peripheral artery disease. New therapeutic options need to be identified for the treatment of hypertension in order to increase the percentage of individuals with controlled BP. There is a growing basic science literature regarding the role of T-cells in the pathogenesis of hypertension and BP control; however, the majority of this literature has been performed exclusively in males despite the fact that both men and women develop hypertension. This is especially problematic since hypertension is well recognized as having distinct sex differences in the prevalence, absolute BP values and molecular mechanisms contributing to the pathophysiology of the disease. The purpose of this article is to review the available literature regarding sex differences in T-cells in hypertension followed by highlighting the potential pathways that may result in sex-specific effects on T-cell activation and differentiation.
Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Caracteres Sexuales , Linfocitos T/citología , Animales , Presión Sanguínea/fisiología , Humanos , Hipertensión/fisiopatología , Factores de RiesgoRESUMEN
Nitric oxide is a critical regulator of blood pressure (BP) and inflammation, and female spontaneously hypertensive rats (SHR) have higher renal nitric oxide bioavailability than males. We hypothesize that female SHR will have a greater rise in BP and renal T cell infiltration in response to nitric oxide synthase (NOS) inhibition than males. Both male and female SHR displayed a dose-dependent increase in BP to the nonspecific NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 2, 5, and 7 mg·kg(-1)·day(-1) for 4 days each); however, females exhibited a greater increase in BP than males. Treatment of male and female SHR with 7 mg·kg(-1)·day(-1) L-NAME for 2 wk significantly increased BP in both sexes; however, prior exposure to L-NAME only increased BP sensitivity to chronic NOS inhibition in females. L-NAME-induced hypertension increased renal T cell infiltration and indices of renal injury in both sexes, yet female SHR exhibited greater increases in Th17 cells and greater decreases in regulatory T cells than males. Chronic L-NAME was also associated with larger increases in renal cortical adhesion molecule expression in female SHR. The use of triple therapy to block L-NAME-mediated increases in BP attenuated L-NAME-induced increases in renal T cell counts and normalized adhesion molecule expression in SHR, suggesting that L-NAME-induced increases in renal T cells were dependent on both increases in BP and NOS inhibition. Our data suggest that NOS is critical in the ability of SHR, females in particular, to maintain BP and limit a pro-inflammatory renal T cell profile.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipertensión/enzimología , Inflamación/enzimología , Riñón/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Moléculas de Adhesión Celular/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Hipertensión/patología , Hipertensión/fisiopatología , Inflamación/inmunología , Inflamación/patología , Inflamación/fisiopatología , Inflamación/prevención & control , Riñón/inmunología , Riñón/patología , Riñón/fisiopatología , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Endogámicas SHR , Factores Sexuales , Linfocitos T/inmunología , Factores de TiempoRESUMEN
Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.
Asunto(s)
Hipertensión , Hipotensión , Animales , Femenino , Masculino , Ratas , Presión Sanguínea/fisiología , Inhibidores Enzimáticos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa , Ratas Endogámicas WKYRESUMEN
Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit â¼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+ ::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+ ::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by â¼1 h and delayed peak of BP and activity by â¼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. AS Cre/+ ::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.
Asunto(s)
Factores de Transcripción ARNTL , Presión Sanguínea , Relojes Circadianos , Conducta Alimentaria , Animales , Masculino , Ratones , Factores de Transcripción ARNTL/genética , Encéfalo/metabolismo , Relojes Circadianos/genética , Corticosterona , Ratones NoqueadosRESUMEN
Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.
Asunto(s)
Relojes Circadianos , Transcriptoma , Masculino , Animales , Ratones , Transcriptoma/genética , Ritmo Circadiano/genética , Relojes Circadianos/genética , Hipotálamo , Envejecimiento/genética , Envejecimiento/metabolismoRESUMEN
Renal ischemia-reperfusion injury is a major cause of acute kidney injury that carries a high mortality rate and increases the risk of later development of hypertension and chronic kidney disease. Although mouse models have contributed much to our understanding of the mechanisms involved, studying aspects of the injury process in vivo remains technically challenging. This study validates the use of noninvasive ultrasound imaging to assess both renal perfusion and vascular adhesion molecule expression following 1-h unilateral renal ischemia in male and female mice. Pulsed-wave Doppler measurements of renal arterial blood velocity revealed renal perfusion recoveries of 56 ± 9% in male and 69 ± 10% in female mice 1 h after the commencing of reperfusion, which is similar to what we have previously published using conventional invasive methodology. At 24 h postischemia, renal perfusion was 40 ± 8% in male and 46 ± 7% in female mice, representing a further significant reduction of perfusion (P(Time) < 0.001). Using ultrasound imaging of a P-selectin-targeted contrast agent, a significant increase in vascular P-selectin protein expression was observed after 1-h reperfusion in the cortex of the postischemic compared with contralateral kidney in both male and female mice (18 ± 5 vs. 3 ± 3 intensity units in male and 30 ± 6 vs. 0 ± 4 in female mice, P(Ischemia) < 0.01). An approximately sixfold increase in P-selectin mRNA was observed ex vivo in the renal vasculature of male and female mice at this time point (P < 0.01). In conclusion, ultrasound represents an effective and noninvasive method for the measurement of both renal perfusion and vascular adhesion molecule expression in mice.
Asunto(s)
Riñón/metabolismo , Selectina-P/metabolismo , Flujo Sanguíneo Regional/fisiología , Arteria Renal/diagnóstico por imagen , Arteria Renal/fisiología , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/metabolismo , Animales , Velocidad del Flujo Sanguíneo/fisiología , Moléculas de Adhesión Celular/metabolismo , Modelos Animales de Enfermedad , Femenino , Riñón/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/fisiopatología , Caracteres Sexuales , Factores de Tiempo , Ultrasonografía Doppler de PulsoRESUMEN
BACKGROUND: Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SSPer1-/-), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure. METHODS: The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm. RESULTS: SSPer1-/- rats had similar mean arterial pressure when fed a normal 0.4% NaCl diet but developed augmented hypertension after three weeks on a high-salt (4% NaCl) diet. Despite being maintained on a normal 12:12 light:dark cycle, SSPer1-/- rats exhibited desynchrony mean arterial pressure rhythms on a high-salt diet, as evidenced by increased variability in the time of peak mean arterial pressure. SSPer1-/- rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SSPer1-/- rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SSPer1-/- rats also exhibited higher plasma aldosterone levels. CONCLUSIONS: Altogether, our findings demonstrate that loss of PER1 in Dahl SS rats causes an array of deleterious effects, including exacerbation of the development of salt-sensitive hypertension and renal damage.
Asunto(s)
Relojes Circadianos , Hipertensión , Enfermedades Renales , Animales , Masculino , Ratas , Presión Sanguínea/fisiología , Relojes Circadianos/genética , Hipertensión/genética , Hipertensión/metabolismo , Riñón/metabolismo , Ratones Noqueados , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratas Endogámicas Dahl , Sodio/metabolismo , Cloruro de Sodio/metabolismo , Cloruro de Sodio Dietético/farmacología , Factores de Transcripción/metabolismoRESUMEN
Nearly every system within the body contains an intrinsic cellular circadian clock. The circadian clock contributes to the regulation of a variety of homeostatic processes in mammals through the regulation of gene expression. Circadian disruption of physiological systems is associated with pathophysiological disorders. Here, we review the current understanding of the molecular mechanisms contributing to the known circadian rhythms in physiological function. This article focuses on what is known in humans, along with discoveries made with cell and rodent models. In particular, the impact of circadian clock components in metabolic, cardiovascular, endocrine, musculoskeletal, immune, and central nervous systems are discussed. © 2021 American Physiological Society. Compr Physiol 11:1-30, 2021.