RESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. METHODS: Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. RESULTS: Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas silencing or dominant negative PBK reduced cytokinesis and the number of cells in the G2/M phase of the cell cycle. CONCLUSIONS: PBK is a newly described target for PAH that is upregulated in proliferating PA smooth muscle cells, where it contributes to proliferation through changes in cytokinesis and cell cycle dynamics to promote medial thickening, fibrosis, increased PA resistance, elevated right ventricular systolic pressure, right ventricular remodeling, and PH.
Assuntos
Hipertensão Arterial Pulmonar , Artéria Pulmonar , Remodelação Vascular , Animais , Humanos , Ratos , Camundongos , Masculino , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Modelos Animais de Doenças , Ratos Sprague-Dawley , Proliferação de Células , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
OBJECTIVE: To investigate whether the sex disparities in type 2 diabetes-associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. RESEARCH DESIGN AND METHODS: We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. RESULTS: Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03-1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). CONCLUSIONS: Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the excess in diabetes-related CVD risk for women but may benefit from intensive BP control.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Hipertensão/epidemiologia , Hipertensão/complicações , Masculino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Anti-Hipertensivos/uso terapêutico , Idoso , Fatores Sexuais , Idade de Início , Pressão Sanguínea/fisiologiaRESUMO
BACKGROUND: Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females. METHODS: 13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography-mass spectrometry (LC/MS). RESULTS: Male SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR. CONCLUSION: Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.
Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Feminino , Masculino , Ratos , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Injúria Renal Aguda/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Inflamação/metabolismo , Isquemia/patologia , Rim/metabolismo , Ratos Endogâmicos SHR , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Red blood cell (RBC) trapping is common in ischemic acute kidney injury (AKI) and presents as densely packed RBCs that accumulate within and engorge the kidney medullary circulation. In this study, we tested the hypothesis that "RBC trapping directly promotes tubular injury independent of extending ischemia time." Studies were performed on rats. Red blood cell congestion and tubular injury were compared between renal arterial clamping, venous clamping, and venous clamping of blood-free kidneys. Vessels were occluded for either 15 or 45 min with and without reperfusion. We found that RBC trapping in the medullary capillaries occurred rapidly following reperfusion from renal arterial clamping and that this was associated with extravasation of blood from congested vessels, uptake of blood proteins by the tubules, and marked tubular injury. To determine if this injury was due to blood toxicity or an extension of ischemia time, we compared renal venous and arterial clamping without reperfusion. Venous clamping resulted in RBC trapping and marked tubular injury within 45 min of ischemia. Conversely, despite the same ischemia time, RBC trapping and tubular injury were minimal following arterial clamping without reperfusion. Confirming the role of blood toward tubular injury, injury was markedly reduced in blood-free kidneys with venous clamping. Our data demonstrate that RBC trapping results in the rapid extravasation and uptake of blood components by tubular cells, causing toxic tubular injury. Tubular toxicity from extravasation of blood following RBC trapping appears to be a major component of tubular injury in ischemic AKI, which has not previously been recognized.
Assuntos
Injúria Renal Aguda , Lesões do Sistema Vascular , Animais , Ratos , Eritrócitos , Rim , IsquemiaRESUMO
BACKGROUND: AngII (angiotensin II)-dependent hypertension causes comparable elevations of blood pressure (BP), aldosterone levels, and renal ENaC (epithelial Na+ channel) activity in male and female rodents. Mineralocorticoid receptor (MR) antagonism has a limited antihypertensive effect associated with insufficient suppression of renal ENaC in male rodents with AngII-hypertension. While MR blockade effectively reduces BP in female mice with salt-sensitive and leptin-induced hypertension, MR antagonism has not been studied in female rodents with AngII-hypertension. We hypothesize that overstimulation of renal MR signaling drives redundant ENaC-mediated Na+ reabsorption and BP increase in female rats with AngII-hypertension. METHODS: We employ a combination of physiological, pharmacological, biochemical, and biophysical approaches to compare the effect of MR inhibitors on BP and ENaC activity in AngII-infused male and female Sprague Dawley rats. RESULTS: MR blockade markedly attenuates AngII-hypertension in female rats but has only a marginal effect in males. Spironolactone increases urinary sodium excretion and urinary sodium-to-potassium ratio in AngII-infused female, but not male, rats. The expression of renal MR and HSD11ß2 (11ß-hydroxysteroid dehydrogenase type 2) that determines the availability of MR to aldosterone is significantly higher in AngII-infused female rats than in males. ENaC activity is ≈2× lower in spironolactone-treated AngII-infused female rats than in males. Reduced ENaC activity in AngII-infused female rats on spironolactone correlates with increased interaction with ubiquitin ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2), targeting ENaC for degradation. CONCLUSIONS: MR-ENaC axis is the primary determinant of excessive renal sodium reabsorption and an attractive antihypertensive target in female rats with AngII-hypertension, but not in males.
Assuntos
Hipertensão , Hipotensão , Feminino , Masculino , Ratos , Camundongos , Animais , Anti-Hipertensivos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Aldosterona/farmacologia , Espironolactona , Pressão Sanguínea , Ratos Sprague-Dawley , Diuréticos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , SódioRESUMO
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.
Assuntos
Hipertensão , Hipotensão , Animais , Feminino , Masculino , Ratos , Pressão Sanguínea/fisiologia , Inibidores Enzimáticos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase , Ratos Endogâmicos WKYRESUMO
Renal function increases in pregnancy due to the significant hemodynamic demands of plasma volume expansion and the growing feto-placental unit. Therefore, compromised renal function increases the risk for adverse outcomes for pregnant women and their offspring. Acute kidney injury (AKI), or sudden loss of kidney function, is a significant event that requires aggressive clinical management. An AKI event in pregnancy, or in the postpartum period, significantly increases the risk of adverse pregnancy events and fetal and maternal mortality. At present, there are significant clinical challenges to the identification, diagnosis, and management of pregnancy-associated AKI due to changing hemodynamics in pregnancy that alter baseline values and to treatment limitations in pregnancy. Emerging data indicate that patients that are considered clinically recovered following AKI, which is currently assessed primarily by return of plasma creatinine levels to normal, maintain risk of long-term complications indicating that current recovery criteria mask the detection of subclinical renal damage. In association, recent large-scale clinical cohorts indicate that a history of AKI predisposes women to adverse pregnancy events even years after the patient is considered recovered from AKI. Mechanisms via which women develop AKI in pregnancy, or develop adverse pregnancy events post-AKI, are poorly understood and require significant study to better prevent and treat AKI in women. © 2023 American Physiological Society. Compr Physiol 13:4869-4878, 2023.
Assuntos
Injúria Renal Aguda , Placenta , Feminino , Humanos , Gravidez , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Injúria Renal Aguda/etiologia , Rim , Fatores de RiscoRESUMO
Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein, is essential for oligodendrocyte maturation and myelination; however, its role in the kidneys or in SOX9 regulation remains unknown. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.
Assuntos
Injúria Renal Aguda , Fatores de Transcrição SOX9 , Animais , Humanos , Camundongos , Injúria Renal Aguda/prevenção & controle , Células Epiteliais/metabolismo , Rim/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Regulação para Cima , Dedos de ZincoRESUMO
Prenatal, perinatal, and adulthood exposure to chronic intermittent hypoxia (IH) increases blood pressure in rodents. Males exposed to chronic IH have higher blood pressure versus females. However, it is unknown if this same-sex difference exists with acute perinatal IH. We tested the hypothesis that acute perinatal IH increases baseline blood pressure and enhances sensitivity to angiotensin II (ANG II)-induced hypertension in male Sprague-Dawley rats. Male and female pups were randomized to control (room air) or IH (10 min of â¼10% O2 for 3 times/day) for the first 8 days of life. IH decreased oxygen saturation, as confirmed via a pulse oximeter. Pups were weaned at postnatal day 21. Blood pressure was measured via telemetry beginning at 14 wk of age and analyzed separately into light and dark phases to assess circadian rhythm. Osmotic minipumps to deliver ANG II were implanted at 15 wk of age. Perinatal IH exposure did not alter baseline blood pressure. One week of ANG II treatment increased blood pressure in light and dark periods in males exposed to IH versus control; there was no effect in females. Blood pressure among the groups was comparable following 2 wk of ANG II infusion. Perinatal IH did not change the circadian rhythm. Following ANG II treatment, indexes of renal injury were measured. Perinatal IH did not alter kidney size, structure, nephron number, or creatinine clearance. These data indicate that acute perinatal IH enhances early ANG II-induced hypertension in males, independent of nephron loss or decreases in body weight or kidney function.NEW & NOTEWORTHY The impact of acute intermittent hypoxia (IH) in early life on blood pressure in adulthood is unknown. This study used a new model exposing female and male rat pups to acute IH in the first 8 days of life, without exposing the dam. Although baseline blood pressure was not altered in adulthood, IH increased susceptibility to angiotensin II hypertension only in males, supporting increased susceptibility of males exposed to IH to a second cardiovascular stressor.
Assuntos
Angiotensina II , Hipertensão , Animais , Feminino , Masculino , Gravidez , Ratos , Angiotensina II/farmacologia , Hipertensão/induzido quimicamente , Hipóxia/complicações , Rim , Ratos Sprague-DawleyRESUMO
Apoptosis is a physiological and anti-inflammatory form of cell death that is indispensable for normal physiology and homeostasis. Several studies have reported aberrant activation of apoptosis in various tissues at the onset of hypertension. However, the functional significance of apoptosis during essential hypertension remains largely undefined. The current study was designed to test the hypothesis that apoptosis contributes to sex differences in blood pressure and the T cell profile in spontaneously hypertensive rats (SHR). Apoptosis was measured in kidney, aorta and spleen of 13-week-old adult hypertensive male and female SHR. Female SHR had greater renal and aortic apoptosis compared to age-matched males; apoptosis in the spleen was comparable between the sexes. Based on well-established sex differences in hypertension, we tested the hypothesis that greater apoptosis in female SHR contributes to the lower BP and pro-inflammatory profile compared to males. Male and female SHR were randomized to receive vehicle or ZVAD-FMK, a cell permeable pan-caspase inhibitor, in established hypertension from 13 to 15 weeks of age or at the onset of hypertension from 6 to 12 weeks or age. Treatment with ZVAD-FMK lowered renal apoptosis in both studies, yet neither BP nor renal T cells were altered in either male or female SHR. These results suggest that apoptosis does not contribute to the control or maintenance of BP in male or female SHR or sex differences in renal T cells.
RESUMO
MicroRNA (miRNA) are small, single strand non-coding RNA molecules involved in the post-transcriptional regulation of target genes. Since their discovery in 1993, over 2000 miRNAs have been identified in humans and there is growing interest in both the diagnostic and therapeutic potential of miRNA. The identification of biomarkers for human disease progression remains an active area of research, and there is a growing number of miRNA and miRNA combinations that have been linked to the development and progression of numerous cardiovascular diseases, including hypertension. In 2010, Chen et al. reported in Clinical Science that cell-free circulating miRNA could serve as novel biomarkers for acute myocardial infarction [1]. In this commentary, we expand on this topic to discuss the potential of using miRNA as biomarkers for hypertension and hypertension-related end-organ damage.
Assuntos
MicroRNA Circulante , Hipertensão , MicroRNAs , Infarto do Miocárdio , Biomarcadores , Regulação da Expressão Gênica , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , MicroRNAs/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genéticaRESUMO
Acute kidney injury (AKI) due to ischemia is a serious and frequent clinical complication with mortality rates as high as 80%. Vascular congestion in the renal outer medulla occurs early after ischemia reperfusion (IR) injury, and congestion has been linked to worsened outcomes following IR. There is evidence implicating both male sex and preexisting hypertension as risk factors for poor outcomes following IR. The present study tested the hypothesis that male spontaneously hypertensive rats (SHR) have greater vascular congestion and impaired renal recovery following renal IR vs. female SHR and normotensive male Sprague-Dawley rats (SD). Thirteen-week-old male and female SHR and SD were subjected to sham surgery or 30 min of warm bilateral ischemia followed by reperfusion. Rats were euthanized 24 h or 7 days post-IR. IR increased renal injury in all groups vs. sham controls at 24 h. At 7 days post-IR, injury remained elevated only in male SHR. Histological examination of SD and SHR kidneys 24 h post-IR showed vascular congestion in males and females. Vascular congestion was sustained only in male SHR 7 days post-IR. To assess the role of vascular congestion on impaired recovery following IR, additional male and female SHR were pretreated with heparin (200 U/kg) prior to IR. Heparin pretreatment reduced IR-induced vascular congestion and improved renal function in male SHR 7 days post-IR. Interestingly, preventing increases in blood pressure (BP) in male SHR did not alter sustained vascular congestion. Our data demonstrate that IR-induced vascular congestion is a major driving factor for impaired renal recovery in male SHR.
Assuntos
Injúria Renal Aguda , Hipertensão , Traumatismo por Reperfusão , Injúria Renal Aguda/patologia , Animais , Feminino , Heparina/uso terapêutico , Hipertensão/tratamento farmacológico , Isquemia/patologia , Rim/patologia , Masculino , Perfusão/efeitos adversos , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologiaRESUMO
Numerous studies have demonstrated a sexual dimorphism in blood pressure (BP) control in spontaneously hypertensive rats (SHR), however the mechanisms remain to be further elucidated. Based on the established role of arachidonic acid metabolites and heme oxygenase (HO) in BP control, we hypothesize that higher BP in male SHR is associated with differential expression in renal HO and arachidonic acid metabolizing enzymes vs. female SHR. Higher BP in male SHR coincided with significant increases in renal cortical superoxide production and thiobarbituric acid reactive substances (TBARs) levels as measures of oxidative stress compared to normotensive female WKY and female SHR. The elevations in BP and oxidative stress in male SHR were also associated with a decrease in cortical heme oxygenase-1 (HO-1) expression when compared to normotensive female WKY. Although there was no sex or strain differences in cortical expression of the epoxyeicosatrienoic acids (EETs) producing enzyme, cytochrome P450 epoxygenase (CYP2C23), in male and female SHR and WKY, SHR had greater expression of the EETs metabolizing enzyme, soluble epoxide hydrolase (sEH) vs. WKY. Cortical expression of the 20-hydroxyeicosatetraenoic acid (20-HETE) producing enzyme, cytochrome P450 hydroxylase (CYP4A), was less in female WKY and SHR compared to strain-matched males and cortical 20-HETE levels were also less in female SHR vs. male SHR. Cortical cyclooxygenase-2 (COX-2) expression was significantly greater in female SHR and WKY vs. males and cortical prostaglandin E2 (PGE2) levels in female SHR was significantly greater than male WKY. In conclusion, our data suggest that sex differences in renal oxidative stress, HO-1 and arachidonic acid metabolizing enzymes could contribute to sexual dimorphism in hypertension in young SHR.
Assuntos
Hipertensão , Caracteres Sexuais , Animais , Ácido Araquidônico/metabolismo , Pressão Sanguínea , Sistema Enzimático do Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Feminino , Heme Oxigenase-1/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Hypertension remains the leading risk factor for cardiovascular disease. Young females tend to be protected from hypertension compared with age-matched males. Although it has become increasingly clear that the immune system plays a key role in the development of hypertension in both sexes, few studies have examined how cytokines mediate hypertension in males versus females. We previously published that there are sex differences in the levels of the cytokine tumor necrosis factor (TNF)-α in spontaneously hypertensive rats (SHR). The goal of this study was to test the hypothesis that TNF-α inhibition with etanercept will lower BP in male and female SHR. However, as male SHR have a more pro-inflammatory status than female SHR, we further hypothesize that males will have a greater decrease in BP with TNF-α inhibition than females. Young adult male and female SHR were administered increasing doses of the TNF-α inhibitor etanercept or vehicle twice weekly for 31 days and BP was continuously measured via telemetry. Following treatment, kidneys and urine were collected and analyzed for markers of inflammation and injury. Despite significantly decreasing renal TNF-α levels, renal phospho-NFκB and urinary MCP-1 excretion, etanercept did not alter BP in either male or female SHR. Interestingly, treatment with etanercept increased urinary excretion of protein, creatinine and KIM-1 in both sexes. These results indicate that TNF-α does not contribute to sex differences in BP in SHR but may be vital in the maintenance of renal health.
Assuntos
Hipertensão , Fator de Necrose Tumoral alfa , Animais , Pressão Sanguínea , Etanercepte/metabolismo , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Feminino , Hipertensão/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: Vascular congestion of the renal medulla-trapped red blood cells in the medullary microvasculature-is a hallmark finding at autopsy in patients with ischemic acute tubular necrosis. Despite this, the pathogenesis of vascular congestion is not well defined. METHODS: In this study, to investigate the pathogenesis of vascular congestion and its role in promoting renal injury, we assessed renal vascular congestion and tubular injury after ischemia reperfusion in rats pretreated with low-dose LPS or saline (control). We used laser Doppler flowmetry to determine whether pretreatment with low-dose LPS prevented vascular congestion by altering renal hemodynamics during reperfusion. RESULTS: We found that vascular congestion originated during the ischemic period in the renal venous circulation. In control animals, the return of blood flow was followed by the development of congestion in the capillary plexus of the outer medulla and severe tubular injury early in reperfusion. Laser Doppler flowmetry indicated that blood flow returned rapidly to the medulla, several minutes before recovery of full cortical perfusion. In contrast, LPS pretreatment prevented both the formation of medullary congestion and its associated tubular injury. Laser Doppler flowmetry in LPS-pretreated rats suggested that limiting early reperfusion of the medulla facilitated this protective effect, because it allowed cortical perfusion to recover and clear congestion from the large cortical veins, which also drain the medulla. CONCLUSIONS: Blockage of the renal venous vessels and a mismatch in the timing of cortical and medullary reperfusion results in congestion of the outer medulla's capillary plexus and promotes early tubular injury after renal ischemia. These findings indicate that hemodynamics during reperfusion contribute to the renal medulla's susceptibility to ischemic injury.
Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Humanos , Isquemia/complicações , Rim/patologia , Medula Renal/irrigação sanguínea , Lipopolissacarídeos , Ratos , Circulação Renal/fisiologia , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controleRESUMO
Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated; however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLRs), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared with females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-wk-old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared with females. However, treatment with TLR4 neutralizing antibody for 2 wk did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicate that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more proinflammatory renal T cell profile in males versus females.
Assuntos
Hipertensão , Caracteres Sexuais , Animais , Pressão Sanguínea/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Receptor 4 Toll-Like/metabolismoRESUMO
Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.
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Receptores de Angiotensina , Acidente Vascular Cerebral , Animais , Cognição , Feminino , Imidazóis , Masculino , Densidade Microvascular , Ratos , Receptor Tipo 2 de Angiotensina , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Sulfonamidas , TiofenosRESUMO
Over the past decade there has been increasing support for a role of the immune system in the development of hypertension. Our lab has previously reported that female spontaneously hypertensive rats (SHRs) have a blood pressure (BP)-dependent increase in anti-inflammatory renal regulatory T cells (Tregs), corresponding to lower BP compared with males. However, little is known regarding the mechanism for greater renal Tregs in females. The current study was designed to test the hypothesis that the greater relative abundance of renal Tregs in female SHR is due to greater Treg production. To test this hypothesis, T cell profiles were measured in the spleen by flow cytometry in male and female SHR at 5 and 14 weeks of age. Splenic Tregs did not differ between males and females, suggesting sex differences in renal Tregs is not due to differences in production. To assess the role of the spleen in sex differences in renal Tregs and BP control, rats were randomized to receive sham surgery (CON) or splenectomy (SPLNX) at 12 weeks of age and implanted with telemeters to measure BP. After 2 weeks, kidneys were harvested for flow cytometric analysis of T cells. Splenectomy increased BP in both sexes after 2 weeks. Renal Tregs decreased in both sexes after splenectomy, abolishing the sex differences in renal Tregs. In conclusion, splenic Tregs were comparable in male and female SHRs, suggesting that sex differences in renal Tregs is due to differences in renal Treg recruitment, not Treg production.