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Hypertension current issue



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Temporal Relationship Between Hyperuricemia and Insulin Resistance and Its Impact on Future Risk of HypertensionNovelty and Significance [Epidemiology/Population]

2017-09-13T12:44:37-07:00

Although hyperuricemia and insulin resistance significantly correlated, their temporal sequence and how the sequence influence on future risk of hypertension are largely unknown. This study assessed temporal relationship between uric acid and insulin resistance and its impact on future risk of hypertension by examining a longitudinal cohort including 8543 subjects aged 20 to 74 years from China, with an average follow-up of 5.3 years. Measurements of fasting uric acid, as well as fasting and 2-hour serum glucose and insulin, were obtained at baseline and follow-up. Indicators of hepatic and peripheral insulin resistance were calculated. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between uric acid and insulin resistance and its impact on follow-up hypertension. After adjusting for covariates, the cross-lagged path coefficients (β1 values) from baseline uric acid to follow-up insulin resistance indices were significantly greater than path coefficients (β2 values) from baseline insulin resistance indices to follow-up uric acid (β1=0.110 versus β2=0.017; P<0.001, for hepatic insulin resistance; β1=−0.208 versus β2=−0.021; P<0.001, for peripheral insulin resistance). The path coefficients from baseline uric acid to follow-up insulin resistance indices in the hypertensive group were significantly greater than that in the normotensive group (P<0.001 for the difference of β1 values in the 2 groups). Insulin resistance partially mediated the effect of uric acid on subsequent hypertension, and the mediation effect of peripheral insulin resistance was significantly greater than that of hepatic insulin resistance (31.3% versus 13.2%; P<0.001, for the difference of mediation effects). These findings provide evidence that higher uric acid levels probably precede insulin resistance, and peripheral insulin resistance likely plays a more important role in the development of hypertension than hepatic insulin resistance does.



Individual and Combined Effects of Dietary Factors on Risk of Incident HypertensionNovelty and Significance [Epidemiology/Population]

2017-09-13T12:44:37-07:00

Dietary intake is pointed as one of the major determinants in hypertension development. Data in the area are mostly obtained from cross-sectional studies. We aimed to investigate the prospective association between (1) individual nutritional factors and (2) adherence to the Dietary Approach to Stop Hypertension and the risk of incident hypertension in a large cohort study. We prospectively examined the incidence of hypertension among 80 426 French adults participating in the NutriNet-Santé cohort study. Self-reported sociodemographic, lifestyle health questionnaires and dietary consumption assessed by three 24-hour records were completed at baseline and yearly thereafter. Associations between quartiles (Q) of nutrients and food groups and adherence to Dietary Approach to Stop Hypertension diet and hypertension risk were assessed by multivariable Cox proportional hazards models. During a mean follow-up of 3.4±2.1 years, 2413 cases of incident hypertension were documented. Dietary intakes of sodium (Q4 versus Q1): hazard ratio (HR)=1.17 (95% confidence interval [CI], 1.02–1.35), potassium: HR=0.82 (95% CI, 0.72–0.94), animal protein: HR=1.26 (95% CI, 1.11–1.43), vegetable protein: HR=0.85 (95% CI, 0.75–0.95), fiber: HR =0.81 (95% CI, 0.71–0.93), magnesium: HR=0.77 (95% CI, 0.67–0.89), fruit and vegetables: HR=0.85 (95% CI, 0.74–0.97), whole grain: HR=0.84(95% CI, 0.76–0.93), nuts: HR=0.72 (95% CI, 0.63–0.83), and red and processed meat: HR=1.25 (95% CI, 1.11–0.42) were associated with risk of hypertension. Besides, adherence to the Dietary Approach to Stop Hypertension was strongly inversely associated with incident hypertension: (Q4 versus Q1) HR=0.66 (95% CI, 0.58–0.75). Our results confirmed the association of several nutritional factors intake and incident hypertension and highlighted that adopting a global healthy diet could strongly contribute to the prevention of hypertension.



Increased Risk of New-Onset Hypertension After Shock Wave Lithotripsy in UrolithiasisNovelty and Significance [Epidemiology/Population]

2017-09-13T12:44:37-07:00

Although shock wave lithotripsy is minimally invasive, earlier studies argued that it may increase patients’ subsequent risk of hypertension and diabetes mellitus. This study evaluated the association between shock wave lithotripsy and new-onset hypertension or diabetes mellitus. The Taiwanese National Health Insurance Research Database was used to identify 20 219 patients aged 18 to 65 years who underwent the first stone surgical treatment (shock wave lithotripsy or ureterorenoscopic lithotripsy) between January 1999 and December 2011. A Cox proportional model was applied to evaluate associations. Time-varying Cox models were applied to evaluate the association between the number of shock wave lithotripsy sessions and the incidence of hypertension or diabetes mellitus. After a median follow-up of 74.9 and 82.6 months, 2028 and 688 patients developed hypertension in the shock wave lithotripsy and ureterorenoscopic lithotripsy groups, respectively. Patients who underwent shock wave lithotripsy had a higher probability of developing hypertension than patients who underwent ureterorenoscopic lithotripsy, with a hazard ratio of 1.20 (95% confidence interval, 1.10–1.31) after adjusting for covariates. The risk increased as the number of shock wave lithotripsy sessions increased. However, the diabetes mellitus risk was similar in the shock wave lithotripsy and ureterorenoscopic lithotripsy groups. Furthermore, the hazard ratio did not increase as the number of shock wave lithotripsy sessions increased. Shock wave lithotripsy consistently increased the incidence of hypertension on long-term follow-up. Therefore, alternatives to urolithiasis treatment (eg, endoscopic surgery or medical expulsion therapy) could avoid the hypertension risk. Furthermore, avoiding multiple sessions of shock wave lithotripsy could also evade the hypertension risk.



Childhood Socioeconomic Status and Arterial Stiffness in AdulthoodNovelty and Significance [Epidemiology/Population]

2017-09-13T12:44:37-07:00

Increasing evidence supports the importance of socioeconomic factors in the development of atherosclerotic cardiovascular disease. However, the association of childhood socioeconomic status (SES) with arterial stiffness in adulthood has not been reported. Our aim was to determine whether higher childhood family-level SES is associated with lower arterial stiffness in adulthood. The analyses were performed using data gathered within the longitudinal Young Finns Study. The sample comprised 2566 participants who had data concerning family SES at ages 3 to 18 years in 1980 and arterial pulse wave velocity and carotid artery distensibility measured 21 or 27 years later in adulthood. Higher family SES in childhood was associated with lower arterial stiffness in adulthood; carotid artery distensibility being higher (β value±SE, 0.029±0.0089%/10 mm Hg; P=0.001) and pulse wave velocity lower (β value±SE, −0.062±0.022 m/s; P=0.006) among those with higher family SES in a multivariable analysis adjusted with age, sex, and conventional childhood cardiometabolic risk factors. The association remained significant after further adjustment for participant’s SES in adulthood (β value±SE, 0.026±0.010%/10 mm Hg; P=0.01 for carotid artery distensibility and β value±SE, −0.048±0.023 m/s; P=0.04 for pulse wave velocity) but attenuated after adjustment for adulthood cardiometabolic risk factors (β value±SE, 0.015±0.008%/10 mm Hg; P=0.08 for carotid artery distensibility and β value±SE, −0.019±0.02 m/s; P=0.38 for pulse wave velocity). In conclusion, we observed an association between higher family SES in childhood and lower arterial stiffness in adulthood. Our findings suggest that special attention could be paid to children from low SES families to prevent cardiometabolic diseases primordially.



Trends in the Prevalence, Awareness, Treatment, and Control of Hypertension Among Young Adults in the United States, 1999 to 2014Novelty and Significance [Epidemiology/Population]

2017-09-13T12:44:37-07:00

Overall hypertension prevalence has not changed in the United States in recent decades although awareness, treatment, and control improved. However, hypertension epidemiology and its temporal trends may differ in younger adults compared with older adults. Our study included 41 331 participants ≥18 years of age from 8 National Health and Nutrition Examination Surveys (1999–2014) and estimated temporal trends of hypertension, awareness, treatment, and control among young adults (age, 18–39 years) compared with middle-age (age, 40–59 years) and older adults (age, ≥60 years). In 2013 to 2014, 7.3% of the US young adults had hypertension. During 1999 to 2014, young adults saw larger increases in hypertension awareness, treatment, and control than did older adults. However, all of these components of hypertension control were lower among young adults compared with middle-aged or older adults (74.7% younger versus 81.9% middle versus 88.4% older for awareness; 50.0% versus 70.3% versus 83.0% for treatment; and 40.2% versus 56.7% versus 54.4% for control). Worse hypertension awareness, treatment, and control in young adults overall were mostly driven by worse measures in young adult men compared with young adult women. More frequent healthcare visits by young adult women explained ≈28% of the sex-related difference in awareness, 60% of the difference in treatment, and 52% of the difference in control. These findings suggest that improved access to and engagement in medical care might improve hypertension control in young adults, particularly young adult men, and reduce life-time cardiovascular risk.



Transcriptome-Wide Analysis Identifies Novel Associations With Blood PressureNovelty and Significance [Genomics]

2017-09-13T12:44:37-07:00

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7–16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes—among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03–1.09; P=5.0×10–5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.



Visit-to-Visit Office Blood Pressure Variability and Cardiovascular Outcomes in SPRINT (Systolic Blood Pressure Intervention Trial)Novelty and Significance [Blood Pressure Variability in SPRINT]

2017-09-13T12:44:37-07:00

Studies of visit-to-visit office blood pressure (BP) variability (OBPV) as a predictor of cardiovascular events and death in high-risk patients treated to lower BP targets are lacking. We conducted a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a well-characterized cohort of participants randomized to intensive (<120 mm Hg) or standard (<140 mm Hg) systolic BP targets. We defined OBPV as the coefficient of variation of the systolic BP using measurements taken during the 3-,6-, 9-, and 12-month study visits. In our cohort of 7879 participants, older age, female sex, black race, current smoking, chronic kidney disease, and coronary disease were independent determinants of higher OBPV. Use of thiazide-type diuretics or dihydropyridine calcium channel blockers was associated with lower OBPV whereas angiotensin-converting enzyme inhibitors or angiotensin receptor blocker use was associated with higher OBPV. There was no difference in OBPV in participants randomized to standard or intensive treatment groups. We found that OBPV had no significant associations with the composite end point of fatal and nonfatal cardiovascular events (n=324 primary end points; adjusted hazard ratio, 1.20; 95% confidence interval, 0.85–1.69, highest versus lowest quintile) nor with heart failure or stroke. The highest quintile of OBPV (versus lowest) was associated with all-cause mortality (adjusted hazard ratio, 1.92; confidence interval, 1.22–3.03) although the association of OBPV overall with all-cause mortality was marginal (P=0.07). Our results suggest that clinicians should continue to focus on office BP control rather than on OBPV unless definitive benefits of reducing OBPV are shown in prospective trials.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062



P2y12 Receptor Promotes Pressure Overload-Induced Cardiac Remodeling via Platelet-Driven Inflammation in MiceNovelty and Significance [Heart]

2017-09-13T12:44:37-07:00

Inflammation plays a critical role in adverse cardiac remodeling and heart failure. The P2y12 receptor is one of the predominant activating receptors for platelets, thus initiating inflammatory responses under various diseases. In this study, we investigated the functional significance of P2y12-mediated platelet activation in pressure overload–induced cardiac remodeling. Notably, P2y12 knockout (P2y12−/−) mice exhibited suppressed transverse aortic constriction–induced changes in cardiac hypertrophy, collagen synthesis, inflammatory cell recruitment, and cardiac dysfunction. Activated platelets and platelet–leukocyte aggregates were markedly downregulated in P2y12 knockout mice compared with wild-type counterparts after transverse aortic constriction. Moreover, bone marrow chimera experiments revealed that wild-type recipients of P2y12 knockout bone marrow markedly improved cardiac function and attenuated cardiac remodeling, reversed by wild-type platelets reinjection. Platelet depletion and P-selectin inhibition mimicked these protective effects by limiting the interaction between activated platelets and leukocytes. Furthermore, activated wild-type platelets directly induced cardiomyocyte hypertrophy and collagen synthesis via α-granule exocytosis, vanished in P2y12 knockout platelets or those administered anti-NSF (N-ethlymalimide-sensitive factor) antibodies. The results suggest that P2y12-mediated platelet activation promotes cardiac remodeling by triggering a series of inflammatory changes and interacting with leukocytes and endotheliocytes.



Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt PathwayNovelty and Significance [Heart]

2017-09-13T12:44:37-07:00

Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding–induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8-knockout or Mfge8-overexpressing mice, the activated Akt/PKB (protein kinase B)–Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II–treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy.



Perivascular Adipose Tissue Angiotensin II Type 1 Receptor Promotes Vascular Inflammation and Aneurysm FormationNovelty and Significance [Aortic Aneurysm]

2017-09-13T12:44:37-07:00

Perivascular adipose tissue exhibits characteristics of active local inflammation, which contributes to the development of atherosclerotic disease as a complication of obesity/metabolic syndrome. However, the precise role of perivascular adipose tissue in the progression of abdominal aortic aneurysm remains unclear. To test the hypothesis that genetic deletion of angiotensin II type 1a (AT1a) receptor in perivascular visceral adipose tissue (VAT) can attenuate aortic aneurysm formation in apolipoprotein E–deficient (ApoE−/−) mice, we performed adipose tissue transplantation experiments by using an angiotensin II–induced aneurysm murine model, in which we transplanted VAT from ApoE−/− or ApoE−/− AT1a−/− donor mice onto the abdominal aorta of ApoE−/− recipient mice. Compared with ApoE−/− VAT transplantation, ApoE−/− AT1a−/− VAT transplantation markedly attenuated aortic aneurysm formation, macrophage infiltration, and gelatinolytic activity in the abdominal aorta. AT1a receptor activation led to the polarization of macrophages in perivascular VAT toward the proinflammatory phenotype. Moreover, osteopontin expression and gelatinolytic activity were considerably lower in ApoE−/− AT1a−/− perivascular VAT than in ApoE−/− perivascular VAT, and angiotensin II–induced osteopontin secretion from adipocytes was eliminated after deletion of AT1a receptor in adipocytes. Notably, induction of macrophage migration by conditioned medium from angiotensin II–stimulated wild-type adipocytes was suppressed by treatment with an osteopontin-neutralizing antibody, and ApoE−/− OPN−/− VAT transplantation more potently attenuated aortic aneurysm formation than ApoE−/− VAT transplantation. Our findings indicate a previously unrecognized effect of AT1a receptor in perivascular VAT on the pathogenesis of abdominal aortic aneurysm.



Endothelial Function Is Impaired in Patients Receiving Antihypertensive Drug Treatment Regardless of Blood Pressure LevelNovelty and Significance [Endothelial Function]

2017-09-13T12:44:37-07:00

Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of <120 mm Hg, 7.5±2.8% for 120–129 mm Hg, 7.1±2.8% for 130–139 mm Hg, and 6.7±2.6% for ≥140 mm Hg; P<0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6±3.1% in treated hypertensives with systolic blood pressure of <120 mm Hg, 4.8±2.7% for 120–129 mm Hg, 4.9±2.8% for 130–139 mm Hg, and 4.5±2.3% for ≥140 mm Hg; P=0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.



All Hypertensive Disorders of Pregnancy Increase the Risk of Future Cardiovascular DiseaseNovelty and Significance [Pregnancy and Hypertension]

2017-09-13T12:44:37-07:00

Hypertensive disorders of pregnancy are associated with vascular dysfunction in the pregnancy and an increased risk of long-term cardiovascular disease (CVD) in the mother. What remains to be understood is whether the length, severity of the disease, the treatment of hypertension in pregnancy, or the subtype of hypertensive disorders of pregnancy are significant predictors of future CVD. We undertook a retrospective cohort study to review all women who gave birth at a tertiary hospital in Sydney between the years 1980 and 1989 (n=31 656). A cohort of women was further defined by having hypertension during the antenatal, intrapartum, or postnatal periods (n=4387). Randomly selected records of women (n=1158) with a hypertensive disorder of pregnancy were individually reviewed to collect data on their pregnancy and pregnancy outcomes. The entire cohort then underwent linkage analysis to future CVDs. Women who presented with gestational hypertension were at greater risk of future hypertension and ischemic heart disease compared with the women who were diagnosed with preeclampsia. There was no significant difference between the women who were treated with antihypertensive medication and the women who did not receive antihypertensive medication or the duration of hypertensive disorders of pregnancy and future admission for CVD, although severity of hypertension tracked with increased risk of future hypertension in all groups. This study demonstrated that all women who present with any of the subtypes of hypertensive disorders in pregnancy are at significant risk of future CVD compared with women who remain normotensive during their pregnancy.



Trimester-Specific Weight Gain and Midpregnancy Diastolic Blood Pressure Rebound During Normotensive PregnancyNovelty and Significance [Pregnancy and Hypertension]

2017-09-13T12:44:37-07:00

The longitudinal exposure–response relationship between trimester-specific gestational weight gain (GWG) and blood pressure (BP) during pregnancy is not well understood. We retrospectively assessed 1112 uncomplicated, normotensive pregnant women whose body weight and BP were measured from 12+0 to 40+0 weeks of gestation from a hospital-based cohort. By using growth curve modeling, a J-shaped pattern dominated diastolic BP (DBP) changing dynamics, with a midpregnancy drop at 20+0 to 22+0 weeks followed by a rebound. Using group-based trajectory modeling, 3 distinctive trajectories of DBP were identified: high–J shaped (18.5%), moderate–J shaped (48.3%), and low–J shaped (33.1%), as well as 3 distinctive GWG trajectories: high increasing (14.7%), moderate increasing (48.6%) and low increasing (36.8%). A temporal coincidence between the maximal rate of GWG and DBP transition from its nadir to rebound was observed during 20+0 to 22+0 weeks. Moreover, women in the high-increasing GWG group had the highest probability of being in the high–J DBP group. The GWG rate during the late midsecond trimester (22+0 to 26+0 weeks) was consistently associated with an elevated DBP level: for every 200 g/wk increase, the multivariable-adjusted odds ratio was 1.27 (95% confidence interval, 1.13–1.43) for the trajectory shift to the high–J group and 1.20 (95% confidence interval, 1.07–1.35) for the occurrence of diastolic prehypertension after 37+0 weeks. Furthermore, adding a trimester-specific GWG rate (22+0 to 26+0 weeks) contributed to the incremental yield for the prediction of diastolic prehypertension after 37+0 weeks. Our results thus provide the timing and extent of gestational weight control relevant to the optimized BP level during pregnancy.



Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive RatsNovelty and Significance [Kidney]

2017-09-13T12:44:37-07:00

The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H2O2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of H2O2 into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure. Together, these data indicate that the salt-induced increases of renal H2O2 in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (IP, 1.5 mg/kg per day) for 21 days reduced salt-induced hypertension from 176.0±9.0 to 153.0±12.0 mm Hg in SS rats but had no effect on blood pressure salt sensitivity in Sprague Dawley treated rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0±35.0 to 37.0±5.0 mg/d and reduced the renal infiltration of T lymphocytes (CD3+) and macrophages (ED1+) in the cortex and medulla. Renal hypertrophy and cell proliferation were also reduced in rapamycin-treated SS rats. We conclude that enhancement of intrarenal H2O2 with a 4.0% NaCl diet stimulates the mTORC1 pathway that is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat.



Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin DegradationNovelty and Significance [Kidney]

2017-09-13T12:44:37-07:00

Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II–induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II–induced TGF-β/Smad3 and NF-κB–mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II–induced TGF-β/Smad3-mediated renal fibrosis and NF-κB–driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II–induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II–induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.



Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat KidneyNovelty and Significance [Kidney]

2017-09-13T12:44:37-07:00

The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1–7) in OZR increased urine flow and urinary Na excretion, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1–7) stimulated NO which was blocked by either of the receptor antagonists. Dual labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive to the reducing β-mercaptoethanol, suggesting involvement of -SH groups in cross-linking. Collectively, the study reveals that AT2R and MasR are colocalized and functionally interdependent in terms of stimulating NO and promoting diuretic/natriuretic response.



Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II LevelNovelty and Significance [Inflammation]

2017-09-13T12:44:37-07:00

IL-10 (interleukin-10) has been suggested to play a protective role in angiotensin II (AngII)–induced cardiovascular disorders. This study examined the role of endogenous IL-10 in salt-sensitive hypertension and renal injury induced by AngII. Responses to chronic AngII (400 ng/min per kilogram body weight; osmotic minipump) infusion were evaluated in IL-10 gene knockout mice fed with either normal salt diet (0.3% NaCl) or high salt (HS; 4% NaCl) diet, and these responses were compared with those in wild-type mice. Normal salt diets or HS diets were given alone for the first 2 weeks and then with AngII treatment for an additional 2 weeks (n=6 in each group). Arterial pressure was continuously monitored by implanted radio-telemetry, and a 24-hour urine collection was performed by metabolic cages on the last day of the experimental period. Basal mean arterial pressure was lower in IL-10 gene knockout mice than in wild-type (98±3 versus 113±3 mm Hg) mice. Mean arterial pressure responses to normal salt/HS alone or to the AngII+normal salt treatment were similar in both strains. However, the increase in mean arterial pressure induced by the AngII+HS treatment was significantly lower in IL-10 gene knockout mice (15±5% versus 37±3%) compared with wild-type mice. Renal tissue endothelial nitric oxide synthase expression (≈3-folds) and urinary excretion of nitric oxide metabolites, nitrate/nitrite (1.2±0.1 versus 0.2±0.02 µmol/L/24 hours) were higher in IL-10 gene knockout mice compared with wild-type mice. These results indicate that an increase in nitric oxide production helps to mitigate salt-sensitive hypertension induced by AngII and suggest that a compensatory interaction between IL-10 and nitric oxide exists in modulating AngII-induced responses during HS intake.