Elevated Plasma Renin Activity Research Articles

Severe metabolic disturbance in an human immunodeficiency virus-exposed newborn: Possible effect of In utero antiretroviral exposure

The use of antiretroviral (ARV) medications has successfully reduced maternal transmission of human immunodeficiency virus (HIV)-1 to newborns, but metabolic and mitochondrial toxicities in newborns continue to be a concern. We report the case of a 10-day-old full-term female infant born to an HIV-positive mother presenting with lethargy and respiratory distress. Maternal ARV medications included nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase strand transcriptase inhibitors (INSTIs). Infant ARV prophylaxis included two NRTIs and a nonnucleoside reverse transcriptase inhibitor. At presentation, laboratory tests were significant for hyponatremia, hyperkalemia, severe metabolic acidosis, and acute kidney injury. She was resuscitated with fluids and a stress dose of hydrocortisone (HC), which resulted in improvement of her condition within 48 h. Adrenal profile on the day of admission revealed elevated levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, aldosterone, and elevated plasma renin activity. HC was tapered and the patient was discharged on the day of life (DOL) 26. Adrenocorticotropic hormone (ACTH) stimulation test off HC for one night that was performed on DOL31 showed a normal cortisol response of 35.8 mcg/dL at 60 min. HC was later discontinued. A repeat ACTH stimulation test off HC for 7 days that was performed on DOL59 yielded a normal cortisol response of 27.6 mcg/dL at 60 min. This report reveals severe metabolic disturbances suggestive of adrenal insufficiency (AI) in a neonate exposed to a combination of ARV medications in utero and postnatally with improvement of symptoms after glucocorticoid treatment. The AI was transient in nature, which resolved after cessation of ARV therapy.

Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.

ObjectiveA high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart.MethodsWistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated.ResultsThe excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs.ConclusionAn excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening.

Neonatal screening for congenital adrenal hyperplasia (CAH) has been conducted in Taiwan since 2000. This study aimed to determine the clinical characteristics of Taiwanese children with CAH due to 21-hydroxylase deficiency (21-OHD) detected by neonatal screening. From 2000 to 2015, 26 neonates (14 boys and 12 girls) with classic 21-OHD detected by neonatal screening and confirmed at National Taiwan University Hospital were enrolled. Among them, 22 were diagnosed as salt wasting (SW) type and four as simple virilizing (SV) type. Through a review of medical records, their clinical presentations, laboratory data, and molecular studies were analyzed. The most common manifestation was hyperpigmentation. All female neonates regardless of 21-OHD type had atypical genitalia, clitoromegaly, and posterior labial fusion. All of the patients had baseline serum 17-hydroxyprogesterone levels higher than normal. Of the 26 patients, 24 had elevated adrenocorticotropic hormone levels, but only four had low serum cortisol levels. The median baseline adrenocorticotropic hormone, 17-hydroxyprogesterone, and androstenedione levels were significantly higher in patients with SW than in those with SV 21-OHD. All patients with SW 21-OHD had elevated plasma renin activity. The most frequent SW 21-OHD mutations were c.293-13C>G and gene deletion, whereas Ile173Asn and c.293-13C>G were the most frequently detected in SV 21-OHD. In Taiwan, neonatal screening effectively leads to the early diagnosis of CAH and reduces fatal adrenal crisis in neonates. This study may provide physicians with a better understanding of the clinical findings among children with early-diagnosed CAH, allowing for better care in the future.

Sepiapterin reductase gene-disrupted mice suffer from hypertension with fluctuation and bradycardia.

(6R)‐l‐erythro‐5,6,7,8‐Tetrahydrobiopterin (BH4) is an essential cofactor for monoamine and nitric oxide (NO) production. Sepiapterin reductase (SPR) catalyzes the final step in BH4 biosynthesis. We analyzed the cardiovascular function of adult Spr gene‐disrupted (Spr −/−) mice for the first time. After weaning, Spr −/− mice suffered from hypertension with fluctuation and bradycardia, while the monoamine contents in these mice were less than 10% of those in the wild‐type mice as a result of BH4 depletion. Heart rate variability analysis indicated the sympathetic dominant state in Spr −/− mice. The endothelium‐dependent vascular relaxation in response to acetylcholine was significantly impaired in Spr −/− mice after sexual maturation (above 4 months old). Protein amounts of α 1 adrenergic receptor and eNOS in the aorta were not altered. Spr −/− mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of Spr −/− mice would be caused by an imbalance of sympathetic and parasympathetic input and impaired nitric oxide production in endothelial cells. We suggest an important role of BH4 and SPR in age‐related hypertension and a possible relationship with the cardiovascular instabilities in autonomic diseases, including Parkinson's disease and spinal cord injury.

OP.LB.02.01] STRATEGY TO OPTIMIZE SODIUM INTAKE FOR INDIVIDUAL PATIENTS

Objective: Most Americans (90%) have dietary sodium intakes between 2.5 and 5.0 g/d. These limits are coterminous with optimal Cardiovascular (CVD) outcomes and, outcomes do not vary within this range. Beyond those limits, CVD risk increases. The health consequences of raising low, or lowering high intakes, is unknown. Thus, for persons at the extremes of sodium intake, we propose a strategy for their identification, dietary remediation, and ongoing health assessment may benefit as much as10% of the nation's population. Design and method: Epidemiological studies linking sodium intake with subsequent CVD were reviewed. History, physical exam, urine and blood tests can identify patients with sodium intakes < 2.5, and > 5.0 g/d. Dietary modification and/or supplementation can alter sodium intake. Although the strategy proposed is experimental, because its components are safe, and its effects readily assessed, it can be safely applied in clinical settings pending feasible rigorous scientific testing. Results: Persons with sodium intake < 2.5 or > 5. g/d can be identified and treated. Restricted diets and elevated Plasma Renin Activity (PRA), or signs of volume depletion, are associated with low sodium intakes < 2.5. Increased CVD risk is also present at sodium intakes >5.0 g/, but only when associated with hypertension. These patients have suppressed PRA. Sequential spot and, finally, 24-hour urine-analyses, can identify those most likely to benefit from optimtimizing sodium intake through a 1.0 g/d dietary change. Urinary sodium, PRA and blood pressure response should be monitored. Randomized trials – ultimately with hard clinical endpoints - must validate these interventions. Conclusions: The sodium intake of most Americans is optimal, yet 10% with intakes <2.5 or >5.0 g/d are at increased CVD risk. Since health consequences of altering dietary sodium are unknown, any intervention to modify intake is experimental and can and should be evaluated through clinical trials. Nevertheless, concerned and informed patients and physicians may seek to improve health outcomes by increasing or decreasing their sodium intakes. We have described a feasible strategy to identify individual patients for whom proven intervention to optimize sodium intake may be beneficial.

Effects of estrogen replacement on stress-induced cardiovascular responses via renin-angiotensin system in ovariectomized rats

The purpose of this study was to determine whether chronic estrogen replacement in ovariectomized rats inhibits the pressor response to psychological stress by attenuating the activation of the renin-angiotensin system. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, the rats were randomly assigned to be implanted subcutaneously with pellets containing either 17β-estradiol (E2) or placebo (Pla). After 4 wk of treatment, the rats underwent cage-switch stress and, in a separate experiment, a subset received an infusion of angiotensin II. The cage-switch stress rapidly elevated blood pressure (BP) and heart rate (HR) as measured by radiotelemetry in both groups. However, the BP and HR responses to the stress were significantly attenuated in the E2 group compared with the Pla group. An angiotensin II type 1 receptor blocker, losartan, given in drinking water, abolished the difference in the pressor response to stress between the two groups. Moreover, the stress-induced elevation in plasma renin activity and angiotensin II concentration was significant in the Pla group, but not in the E2 group. In addition, the expression of renin mRNA in the kidney was lower in the E2 group relative to the Pla group. Finally, we found that intravenous angiotensin II infusion increased BP and decreased HR to a similar degree in both groups. These results suggest that the inhibitory effects of estrogen on psychological stress-induced activation of the renin-angiotensin system could be at least partially responsible for the suppression of the pressor responses to psychological stress seen in estrogen-replaced ovariectomized rats.

Neural Control of Blood Pressure in Chronic Intermittent Hypoxia.

Sleep apnea (SA) is increasing in prevalence and is commonly comorbid with hypertension. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in SA, and through this paradigm, the mechanisms that underlie SA-induced hypertension are becoming clear. Cyclic hypoxic exposure during sleep chronically stimulates the carotid chemoreflexes, inducing sensory long-term facilitation, and drives sympathetic outflow from the hindbrain. The elevated sympathetic tone drives hypertension and renal sympathetic activity to the kidneys resulting in increased plasma renin activity and eventually angiotensin II (Ang II) peripherally. Upon waking, when respiration is normalized, the sympathetic activity does not diminish. This is partially because of adaptations leading to overactivation of the hindbrain regions controlling sympathetic outflow such as the nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM). The sustained sympathetic activity is also due to enhanced synaptic signaling from the forebrain through the paraventricular nucleus (PVN). During the waking hours, when the chemoreceptors are not exposed to hypoxia, the forebrain circumventricular organs (CVOs) are stimulated by peripherally circulating Ang II from the elevated plasma renin activity. The CVOs and median preoptic nucleus chronically activate the PVN due to the Ang II signaling. All together, this leads to elevated nocturnal mean arterial pressure (MAP) as a response to hypoxemia, as well as inappropriately elevated diurnal MAP in response to maladaptations.

Co-inhibition of Angiotensin II Receptor and Endothelin-1 Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice

Background/Aims: Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) may play important roles in renal fibrosis in the obstructed kidney. However, there have been few clear demonstrations of a relationship between their activation and additive or synergistic roles in renal fibrosis. We investigated the protective roles and relationship between renal RAS and ET-1 in unilateral ureteral obstruction (UUO) mice. Methods: 8-week-old male C57BL/6 mice were divided into seven groups: sham, bosentan+sham, valsartan+sham, vehicle+UUO, bosentan+UUO, valsartan+UUO, and valsartan+bosentan+UUO. Valsartan and bosentan were administered orally using an NG tube (valsartan 10 mg/kg/day, bosentan 100 mg/kg/day for 8 days, after which the molecular and structural kidney parameters were evaluated. Bosentan treatment elevated plasma renin activity, renal renin, and AT1R expression in UUO mice. Results: Although valsartan decreased plasma ET-1 in these mice, it did not affect ET(A) or ET(B) in their kidneys. Co-treatment with valsartan and bosentan decreased ET-1 in these mice compared to the single treatments. Bosentan, but not valsartan, elevated eNOS expression in their kidneys. Co-treatment with valsartan and bosentan reduced TGF-β, α-SMA, and collagen IV expression, and the Masson's trichrome stained area in their kidneys. Conclusions: Bosentan and valsartan acted complementarily, and co-treatment with both drugs had an additive protective effect against renal fibrosis.

Biochemical and histological impact of direct renin inhibition by aliskiren on myofibroblasts activation and differentiation in bleomycin induced pulmonary fibrosis in adult mice.

Aliskiren is a drug classified as a direct renin inhibitor. The renin-angiotensin system plays an important role in pulmonary fibrogeneses. This study aimed to investigate the impact of aliskiren on pulmonary fibrosis induced by bleomycin. Forty adult mice were divided into group I (control), group II (aliskiren 25mg/kg/day IP), group III (bleomycin 0.035U/g intraperitoneally twice weekly for 4 weeks) and group IV (aliskiren+bleomycin). Plasma renin activity (PRA), lung content of hydroxyproline and transforming growth factor-β1 (TGF-β1) were assayed. Lung paraffin sections were prepared for histological study and immunohistochemical detection of alpha smooth muscle actin (αSMA) as a marker for myofibroblasts activation and differentiation. Bleomycin induced a significant elevation of PRA with a significant increase in hydroxyproline and TGF-β1 in group III. Microscopically, pulmonary fibrosis was evident in the form of areas of collapsed alveoli, intense inflammatory cells infiltrations, excess accumulation of collagen, and excessively encountered αSMA positively immune-stained myofibroblasts, compared to a negative immune-reaction in groups I and II. In group IV, aliskiren resulted in a significant decrease in PRA, TGF-β1 and hydroxyproline, with an attenuation of pulmonary fibrosis and a decrease in αSMA positively immune-stained myofibroblasts. In conclusion, renin inhibition by aliskiren attenuated pulmonary fibrosis through decreasing TGF-β1 and myofibroblasts activation and differentiation.

Estradiol replacement attenuates stress‐induced pressor response by regulating renin‐angiotensin system in ovariectomized rats

We examined whether chronic estrogen replacement has suppressive effects on psychological stress‐induced pressor response by attenuating renin‐angiotensin system (RAS) in ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, the rats were assigned either to a placebo‐treated (Pla) group or a group treated with 17β‐estradiol (E2) subcutaneously implanted with either pellet. Two wk later, they were implanted with radiotelemetry devices for blood pressure (BP) and heart rate (HR) measurements, and the half of them were denervated renally. These rats underwent cage‐switch stress 2 wk after the operation. The stress elevated the BP and HR rapidly and continuously both in the Pla and E2 groups. However, these responses to the stress were attenuated significantly in the E2 group compared with the Pla group. An angiotensin II type 1 receptor blocker, losartan, abolished the difference in the BP response to the stress between the two groups. In addition, the stress induced elevation of plasma renin activity and angiotensin II concentration only in the Pla group, but not in the E2 group. Furthermore, the renal sympathetic nerve denervation attenuated the pressor response in the Pla group. These results suggest that estradiol replacement attenuates psychological stress‐induced pressor response by suppressing RAS activation in ovariectomized rats.

Abstract 12842: Both Hyponatremia and Elevated Plasma Renin Activity Are Independent and Additive Cardiovascular Risk Factors in Patients With Angiographically Proven Coronary Artery Disease (CAD): The Intermountain Heart Collaborative Study

Background: Several studies have documented an increased risk of future major adverse cardiovascular events (MACE) among CAD patients with elevated baseline plasma renin activity (PRA). One of the proposed mechanisms of elevated PRA is sodium depletion - hyponatremia. However, the relationship between PRA and hyponatremia is not well defined. Methods: A total of 1,781 pts with angiographic CAD (&gt;50% stenosis) enrolled in the Intermountain Heart Collaborative Study were evaluated. Pts were excluded if they had a history of myocardial infarction (MI), heart failure (HF), left ventricular ejection fraction (EF) &lt;45% or were discharged on beta blocker therapy. Baseline sodium levels were stratified between low (&lt;135 mm/L) and normal (≥135 mm/L), and PRA between elevated (&gt;2.3 ng/ml/h) and low (≤2.3 ng/ml/h) risk categories. The independent associations between these categories and MACE (death, MI, HF hospitalization, stroke and new onset renal failure) at five years were determined by multivariable Cox hazard regression analysis. Results: The mean pt age was 65.5 years; most pts were men (73.2%) and hypertensive (70.4%). Overall, PRA was elevated in 940 (52.8%) of the pts and sodium was low in 42 (2.4%) of the pts. The prevalence of elevated PRA was greater among pts with low sodium (66.7% versus 52.4% [p=0.07]). Five-year incidence of MACE was higher among pts with low sodium (61.9% versus 40.7%, p=0.006) and also among those with elevated PRA (43.7% versus 38.3%, p=0.02). After adjustment for baseline characteristics, among pts with low sodium, elevated PRA did not predict an increase in MACE (adjusted hazard ratio (HR)=0.72, p=0.53). However, among those with normal sodium, elevated PRA trended toward an association with MACE (HR=1.14, p=0.08). Conclusion: Among stable pts with angiographically documented CAD, both hyponatremia and elevated PRA are independently associated with future adverse cardiovascular events, although much of the adverse effect of elevated PRA may be explained by the concomitant presence of hyponatremia. The underlying physiology of these findings and its potential implications to future medical management of these pts deserves further study.

Paraneoplastic secondary hypertension due to a renin-secreting desmoplastic small round cell tumor: A case report.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy with a poor outcome that occurs in adolescents and young adults; <200 cases of DSRCT have been reported. Renin-producing tumors are also rare and cases of extrarenal renin-producing tumors are even rarer. The present study describes the case of a 20-year-old male that was diagnosed with DSRCT and presented with severe hypertension and hypokalemia, as well as metabolic alkalosis. The plasma renin activity (PRA) level was identified to be markedly elevated (normal range in standing and supine positions, 1.3–4.0 ng/ml/h and 0.15–2.33 ng/ml/h, respectively) and the plasma aldosterone level was also increased (normal range in standing and supine positions, 4.0–31.0 ng/dl and 1.0–1.6 ng/dl, respectively). The symptoms of the patient were consistent with the renin-secreting tumor triad, which comprises hypertension, hypokalemia and elevated PRA. Paraneoplastic syndromes must always be considered in cancer patients exhibiting unusual clinical findings, despite their rarity. The current patient was diagnosed with paraneoplastic secondary hypertension due to the presence of disseminated renin-secreting DSRCT. The patient was treated with the VAC/IE regimen (vincristine, adriamycin, cyclophosphamide, ifosfamide and etoposide) for six cycles. Following this treatment, the serum renin and aldosterone levels fell to within the normal range and the patient’s blood pressure was normalized without antihypertensive medication. Although an immunohistochemical evaluation of renin was not conducted as the sample size was inadequate, the present study demonstrated that the tumor had produced renin. The biosynthesis of renin was identified by the presence of mRNA that coded for the renin precursor, which was observed in the ascites of the patient. The current study describes, to the best of our knowledge, the first reported case of paraneoplastic secondary hypertension in a patient presenting with a renin-producing DSRCT.

Identification of bona fide alternative renin transcripts expressed along cortical tubules and potential roles in promoting insulin resistance in vivo without significant plasma renin activity elevation.

Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5' variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the Ren2 gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the Ren1C/D gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform.

Pitting type of pretibial edema in a patient with silent thyroiditis successfully treated by angiotensin II receptor blockade

Patient: Female, 56Final Diagnosis: Thyroiditis – silentSymptoms: Palpitations • pretibial pitting edema • short of breath • sweatingMedication: —Clinical Procedure: —Specialty: Endocrinology and MetabolicObjective:Unknown etiologyBackground:Hyper- or hypothyroidism sometimes causes pretibial myxedema characterized by non-pitting infiltration of a proteinaceous ground substance. However, in those patients, the “pitting” type of pretibial edema as a result of increased sodium and fluid retention or vascular hyper-permeability rarely occurs, except in cases complicated by heart failures due to severe cardiomyopathy or pulmonary hypertension.Case Report:A 56-year-old woman developed bilateral pretibial pitting edema, followed by occasional sweating, palpitations, and shortness of breath, which persisted for more than 2 months. The diagnosis of hyperthyroidism due to silent thyroiditis was supported by elevated levels of free thyroxine (T4) and triiodothyronine (T3), with a marked decrease in thyroid-stimulating hormone (TSH), and the negative results for TSH receptor antibodies with typical findings of destructive thyrotoxicosis. Despite her “pitting” type of pretibial edema, a chest radio-graph demonstrated the absence of cardiomyopathy or congestive heart failure. Oral administration of angiotensin II receptor blocker (ARB) was initiated for her systolic hypertension, with a relatively higher elevation of plasma renin activity compared to that of the aldosterone level. Although the symptoms characteristic to hyperthyroidism, such as increased sweating, palpitations and shortness of breath, slowly improved with a spontaneous resolution of the disease, ARB quickly resolved the pretibial pitting edema shortly after the administration..Conclusions:In this case, increased activity of the renin-angiotensin-aldosterone system stimulated by thyroid hormone was likely responsible for the patient’s pitting type of edema. The pharmacological blockade of the renin-angiotensin-aldosterone system was thought to be effective for the quick resolution of the symptom.

Surgical Revasculization for Pediatric Renovascular Hypertension Caused by Fibromuscular Dysplasia

A 4-year male was referred to our hospital for high fever. Incidentally, abnormally high blood pressure was detected. A thorough examination revealed severe stenosis at the origin of two left renal arteries and elevation of plasma renin activity as well as aldosterone level. Some lesions of previous asymptomatic brain bleeding were also revealed. Instead of using prosthetic materials, we transected renal arteries and directly anastomosed them to abdominal aorta, expecting subsequent growth of native vessels. The postoperative course was uneventful. The plasma renin activity and aldosterone level as well as the dose of antihypertensive drug decreased significantly after the operation.

Abstract 192: Activation of Kidney Renin-angiotensin System (RAS) and Renoprotective Effects of Direct Renin Inhibition (DRI) in Glomerulonephritis

The development of glomerulonephritis causes glomerular injury and reduced renal function and is associated with increased renin release. The aims of this study were to demonstrate activation of intrarenal RAS in glomerulonephritis and determine the effects of DRI with aliskiren on progression of glomerulonephritis associated renal injury induced by administration of an anti-Thy1.1 antibody. We divided rats into 3 groups; control group, anti-Thy1.1 glomerulonephritis group and anti-Thy1.1 glomerulonephritis treated with aliskiren (30 mg/kg/day) group. In the anti-Thy1.1 rats, protein excretion and micro albumin excretion levels increased markedly after anti-Thy1.1 antibody injection. The increases in protein (94.7 ± 13.0 mg/day) and micro albumin (7.5 ± 2.6 mg/day) excretions were attenuated by aliskiren treatment (43.6 ± 4.5 mg/day of protein and 2.6 ± 0.7 mg/day of micro albumin). The glomerular expansion score was significantly higher in the anti-Thy1.1 group compared to the control group. The anti-Thy1.1 group also showed elevation of intrarenal TGF-β and PAI-1 mRNA levels compared with control rats. The progression of glomerular expansion and elevation of these mRNA levels was prevented by aliskiren. Importantly, the anti-Thy1.1 group had markedly increased urinary angiotensinogen (AGT) excretion at days 3 (3102.9 ± 683.8 ng/day), but these changes were markedly suppressed by aliskiren treatment (441.3 ± 104.8 ng/day). AGT protein expression in the kidney was significantly lower in the aliskiren treatment group compared with anti-Thy1.1 group (western blot, 0.8 ± 0.04 and immunohistochemistry, 0.7 ± 0.11 relative to anti-Thy1.1 group). Furthermore, plasma renin activity (PRA) and plasma angiotensin (Ang) II levels were significantly increased in the anti-Thy1.1 group and aliskiren treatment prevented the elevation of PRA and plasma Ang II. Anti-Thy1.1 antibody also elicited left ventricular hypertrophy and fibrosis, which were not ameliorated by aliskiren. These results demonstrate that DRI prevents or reduces intrarenal RAS activation and glomerular injury in progressive glomerulonephritis. Accordingly, DRI may be an effective approach to treat glomerulonephritis as well as other intrarenal RAS associated kidney diseases.

Aldosterone Synthase Inhibition in Hypertension

Hypertension is an established risk factor for stroke, premature coronary artery disease and heart failure. Control of elevated blood pressure has been shown to result in significant reduction of cardiovascular risk. Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), not only causes salt and water reabsorbtion in the kidneys through its effect on the mineralocorticoid hormone receptor (MR), but also an MR-independent effect, not regulated by conventional MR blockade. Although many pharmacological agents target different levels of the RAAS cascade, these generally result in elevated renin concentration and plasma renin activity. This upstream feedback response subsequently results in elevated levels of angiotensin II, a potent vasoconstrictor and stimulus to aldosterone release. This aldosterone breakthrough counteracts the long-term blood pressure-lowering effect of these agents. Therefore the development of a new class of pharmacologic agents that directly inhibit the production of aldosterone may prove clinically useful in reducing aldosterone and thereby controlling elevated blood pressure.

Pseudohypoaldosteronism type 1: clinical features and management in infancy

SummaryType 1 pseudohypoaldosteronism (PHA) is a rare heterogeneous group of disorders characterised by resistance to aldosterone action. There is resultant salt wasting in the neonatal period, with hyperkalaemia and metabolic acidosis. Only after results confirm isolated resistance to aldosterone can the diagnosis of type 1 PHA be confidently made. Type 1 PHA can be further classified into i) renal type 1 (autosomal dominant (AD)) and ii) multiple target organ defect/systemic type 1 (autosomal recessive (AR)). The aim of this case series was to characterise the mode of presentation, management and short-term clinical outcomes of patients with PHA type 1. Case notes of newly diagnosed infants presenting with PHA type 1 were reviewed over a 5-year time period. Seven patients were diagnosed with PHA type 1. Initial presentation ranged from 4 to 28 days of age. Six had weight loss as a presenting feature. All subjects had hyperkalaemia, hyponatraemia, with elevated renin and aldosterone levels. Five patients have renal PHA type 1 and two patients have systemic PHA type, of whom one has had genetic testing to confirm the AR gene mutation on the SCNN1A gene. Renal PHA type 1 responds well to salt supplementation, whereas management of patients with systemic PHA type 1 proves more difficult as they are likely to get frequent episodes of electrolyte imbalance requiring urgent correction.Learning points Patients with type 1 PHA are likely to present in the neonatal period with hyponatraemia, hyperkalaemia and metabolic acidosis and can be diagnosed by the significantly elevated plasma renin activity and aldosterone levels.The differential diagnosis of type 1 PHA includes adrenal disorders such as adrenal hypoplasia and congenital adrenal hyperplasia; thus, adrenal function including cortisol levels, 17-hydroxyprogesterone and a urinary steroid profile are required. Secondary (transient) causes of PHA may be due to urinary tract infections or renal anomalies; thus, urine culture and renal ultrasound scan are required respectively.A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing.Management of renal PHA type 1 is with sodium supplementation, and requirements often decrease with age.Systemic PHA type 1 requires aggressive and intensive fluid and electrolyte management. Securing an enteral feeding route and i.v. access are essential to facilitate ongoing therapy.In this area of the UK, the incidence of AD PHA and AR PHA was calculated to be 1:66 000 and 1:166 000 respectively.

First Clinical Experience with TRV027: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

TRV027 is a novel β-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating β-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro. This profile suggests that TRV027 may have unique benefits in acute heart failure, a condition associated with renin-angiotensin system activation. A first-time-in-human study was conducted with ascending doses of TRV027 to explore its tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers. Subjects' salt intake was restricted to stimulate RAS activation. In this study TRV027 was safe and well tolerated with a short-half-life (ranging between 2.4 and 13.2 minutes) and dose-proportional increases in systemic exposure. Consistent with the pre-clinical findings, TRV027 reduced blood pressure to a greater degree in subjects with RAS activation, measured as elevated plasma renin activity, than in those with normal PRA levels. This study in sodium-restricted healthy subjects suggests that TRV027 will successfully target a core mechanism of acute heart failure pathophysiology. Further clinical studies with TRV027 in patients with heart failure are underway.

The Influence of Long Term Hydrochlorothiazide Administration on the Relationship between Renin-Angiotensin-Aldosterone System Activity and Plasma Glucose in Patients with Hypertension

Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.