Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats. METHODS: Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry. RESULTS: Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1-7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney. CONCLUSION: RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.

The Role of Chemerin in Metabolic and Cardiovascular Disease: A Literature Review of Its Physiology and Pathology from a Nutritional Perspective.

Chemerin is a novel adipokine that plays a major role in adipogenesis and lipid metabolism. It also induces inflammation and affects insulin signaling, steroidogenesis and thermogenesis. Consequently, it likely contributes to a variety of metabolic and cardiovascular diseases, including atherosclerosis, diabetes, hypertension and pre-eclampsia. This review describes its origin and receptors, as well as its role in various diseases, and subsequently summarizes how nutrition affects its levels. It concludes that vitamin A, fat, glucose and alcohol generally upregulate chemerin, while omega-3, salt and vitamin D suppress it. Dietary measures rather than drugs acting as chemerin receptor antagonists might become a novel tool to suppress chemerin effects, thereby potentially improving the aforementioned diseases. However, more detailed studies are required to fully understand chemerin regulation.

Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia.

BACKGROUND: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia. METHODS: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts. RESULTS: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine. CONCLUSIONS: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.

Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms.

Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia.

A low aldosterone/renin ratio and high soluble ACE2 associate with COVID-19 severity.

BACKGROUND: The severity of COVID-19 after SARS-CoV-2 infection is unpredictable. Angiotensin-converting enzyme-2 (ACE2) is the receptor responsible for coronavirus binding, while subsequent cell entry relies on priming by the serine protease TMPRSS2 (transmembrane protease, serine 2). Although renin-angiotensin-aldosterone-system (RAAS) blockers have been suggested to upregulate ACE2, their use in COVID-19 patients is now considered well tolerated. The aim of our study was to investigate parameters that determine COVID-19 severity, focusing on RAAS-components and variation in the genes encoding for ACE2 and TMPRSS2. METHODS: Adult patients hospitalized due to SARS-CoV-2 infection between May 2020 and October 2020 in the Haga Teaching Hospital were included, and soluble ACE2 (sACE2), renin, aldosterone (in heparin plasma) and polymorphisms in the ACE2 and TMPRSS2 genes (in DNA obtained from EDTA blood) were determined. MEASUREMENTS AND MAIN RESULTS: Out of the 188 patients who were included, 60 were defined as severe COVID-19 (ICU and/or death). These patients more often used antidiabetic drugs, were older, had higher renin and sACE2 levels, lower aldosterone levels and a lower aldosterone/renin ratio. In addition, they displayed the TMPRSS2-rs2070788 AA genotype less frequently. No ACE2 polymorphism-related differences were observed. Multivariate regression analysis revealed independent significance for age, sACE2, the aldosterone/renin ratio, and the TMPRSS2 rs2070788 non-AA genotype as predictors of COVID-19 severity, together yielding a C-index of 0.79. Findings were independent of the use of RAAS blockers. CONCLUSION: High sACE2, a low aldosterone/renin ratio and having the TMPRSS2 rs2070788 non-AA genotype are novel independent determinants that may help to predict COVID-19 disease severity. TRIAL REGISTRATION: retrospectively registered.

Accurate Prediction of Total PlGF (Placental Growth Factor) From Free PlGF and sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1): Evidence for Markedly Elevated PlGF Levels in Women With Acute Fatty Liver of Pregnancy.

[Figure: see text].

Angiogenic markers during preeclampsia: Are they associated with hypertension 1 year postpartum?

OBJECTIVES: Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery. METHODS: This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement. RESULTS: Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27-33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2-4.4], p = 0.97). CONCLUSION: Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia.

PAPP-A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia.

Background We aimed to evaluate the value of inhibin A and PAPP-A2 (pregnancy-associated plasma protein-A2) as novel biomarkers in the prediction of preeclampsia-related complications and how they compare with angiogenic biomarkers. Methods and Results Making use of a secondary analysis of a prospective, multicenter, observational study, intended to evaluate the usefulness of sFlt-1 (soluble Fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio, we measured inhibin A and PAPP-A2 levels in 524 women with suspected/confirmed preeclampsia. Women had a median gestational age of 35 weeks (range, 20-41 weeks) while preeclampsia occurred in 170 (32%) women. Levels of inhibin A and PAPP-A2 were significantly increased in women with preeclampsia and in maternal perfusate of preeclamptic placentas. Inhibin A and PAPP-A2 (C-index = 0.73 and 0.75) significantly improved the prediction of maternal complications when added on top of the traditional criteria; gestational age, parity, proteinuria, and diastolic blood pressure (C-index = 0.60). PAPP-A2 was able to improve the C-index from 0.75 to 0.77 when added on top of the sFlt-1/PlGF ratio for the prediction of maternal complications. To discriminate fetal/neonatal complications on top of traditional criteria, inhibin A and PAPP-A2 showed additive value (C-index = 0.79 to 0.80 and 0.82, respectively) but their discriminative ability remained inferior to that of sFlt-1/PlGF ratio or PlGF. Interestingly, the PAPP-A2/PlGF ratio alone showed remarkable value to predict pregnancy complications, being superior to sFlt-1/PlGF ratio in the case of maternal complications. Conclusions Inhibin A and PAPP-A2 show significant potential to predict preeclampsia-related pregnancy complications and might prove beneficial on top of the angiogenic markers.

Mycophenolate Mofetil Attenuates DOCA-Salt Hypertension: Effects on Vascular Tone.

Inflammation is increasingly recognized as a driver of hypertension. Both genetic and pharmacological inhibition of B and T cells attenuates most forms of experimental hypertension. Accordingly, the immunosuppressive drug mycophenolate mofetil (MMF) reduces blood pressure in the deoxycorticosterone acetate (DOCA-) salt model. However, the mechanisms by which MMF prevent hypertension in the DOCA-salt model remain unclear. Recent studies indicate that immunosuppression can inhibit sodium transporter activity in the kidney, but its effect on vascular tone is not well characterized. Therefore, the aim of the present study was to analyze the vascular and renal tubular effects of MMF in the DOCA-salt model in rats (4 weeks without uninephrectomy). Co-treatment with MMF attenuated the rise in blood pressure from day 11 onward resulting in a significantly lower telemetric mean arterial pressure after 4 weeks of treatment (108 ± 7 vs. 130 ± 9 mmHg, P < 0.001 by two-way analysis of variance). MMF significantly reduced the number of CD3+ cells in kidney cortex and inner medulla, but not in outer medulla. In addition, MMF significantly reduced urinary interferon-γ excretion. Vascular tone was studied ex vivo using wire myographs. An angiotensin II type 2 (AT2) receptor antagonist blocked the effects of angiotensin II (Ang II) only in the vehicle group. Conversely, L-NAME significantly increased the Ang II response only in the MMF group. An endothelin A receptor blocker prevented vasoconstriction by endothelin-1 in the MMF but not in the vehicle group. MMF did not reduce the abundances of the kidney sodium transporters NHE3, NKCC2, NCC, or ENaC. Together, our ex vivo results suggest that DOCA-salt induces AT2 receptor-mediated vasoconstriction. MMF prevents this response and increases nitric oxide availability. These data provide insight in the antihypertensive mechanism of MMF and the role of inflammation in dysregulating vascular tone.

Angiogenic Markers Predict Pregnancy Complications and Prolongation in Preeclampsia: Continuous Versus Cutoff Values.

To assess the incremental value of a single determination of the serum levels of sFlt-1 (soluble Fms-like tyrosine kinase 1) and PlGF (placental growth factor) or their ratio, without using cutoff values, for the prediction of maternal and fetal/neonatal complications and pregnancy prolongation, 620 women with suspected/confirmed preeclampsia, aged 18 to 48 years, were included in a prospective, multicenter, observational cohort study. Women had singleton pregnancies and a median pregnancy duration of 34 (range, 20-41) weeks. Complications occurred in 118 women and 248 fetuses. The median duration between admission and delivery was 12 days. To predict prolongation, PlGF showed the highest incremental value (R2=0.72) on top of traditional predictors (gestational age at inclusion, diastolic blood pressure, proteinuria, creatinine, uric acid, alanine transaminase, lactate dehydrogenase, and platelets) compared with R2=0.53 for the traditional predictors only. sFlt-1 showed the highest value to discriminate women with and without maternal complications (C-index=0.83 versus 0.72 for the traditional predictors only), and the sFlt-1/PlGF ratio showed the highest value to discriminate fetal/neonatal complications (C-index=0.86 versus 0.78 for the traditional predictors only). Applying previously suggested cutoff values for the sFlt-1/PlGF ratio yielded lower incremental values than applying continuous values. In conclusion, sFlt-1 and PlGF are strong and independent predictors for days until delivery along with maternal and fetal/neonatal complications on top of the traditional criteria. Their use as continuous variables (instead of applying cutoff values for different gestational ages) should now be tested in a prospective manner, making use of an algorithm calculating the risk of an individual woman with suspected/confirmed preeclampsia to develop complications.

The sFlt-1/PlGF ratio associates with prolongation and adverse outcome of pregnancy in women with (suspected) preeclampsia: analysis of a high-risk cohort.

OBJECTIVE: To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE. STUDY DESIGN: Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of ≥85 was defined as a positive test. RESULTS: A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was <85 (false negative), whereas in 7% (n=3) of patients without clinical PE the ratio was ≥85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age <34 weeks, the adverse outcome risk was 11 times increased on the basis of clinical PE, and 30 times on the basis of an elevated ratio (P=0.036). CONCLUSION: The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy.

The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia.

Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation.

Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.

Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors.

Methodologic issues in the measurement of urinary renin.

BACKGROUND AND OBJECTIVES: Alge et al. recently reported that urinary renin may be a prognostic biomarker for AKI after cardiac surgery. However, their urinary renin levels far exceeded published plasma renin levels, whereas normally, urinary renin is <10% of plasma renin. This result raises questions about the specificity of the new Quantikine Renin ELISA Kit used in the work by Alge et al., which is claimed to detect total renin (i.e., renin and prorenin). Therefore, this study tested this assay. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma and urine from 30 patients with hypertension, diabetes, or preeclampsia and 10 healthy pregnant women (randomly selected from sample sets obtained earlier to investigate urinary renin-angiotensin system components) were used to compare the ELISA with a validated renin immunoradiometric assay and an in-house enzyme kinetic assay. Measurements were performed before and after in vitro prorenin activation, representing renin and total renin, respectively. RESULTS: Total renin measurements by ELISA, immunoradiometric assay, and enzyme kinetic assay were highly correlated. However, ELISA results were consistently ≥10-fold higher. The ELISA standard yielded low to undetectable levels in the immunoradiometric assay and enzyme kinetic assay, except after prorenin activation, when the results were ≥10-fold lower than the ELISA results. In plasma, prorenin activation increased ELISA results by 10%-15%. Urine contained no detectable prorenin. CONCLUSIONS: The ELISA renin kit standard is prorenin, and its immunoreactivity and enzymatic activity after conversion to renin do not match the International Reference Preparation of human renin that has been used to validate previous immunoradiometric assays and enzyme kinetic assays; in fact, they are at least 10-fold lower, and thus, any measurements obtained with this ELISA kit yield levels that are at least 10-fold too high. The ELISA antibodies detect both renin and prorenin, with a preference for the former. Given these inconsistencies, urinary renin levels should be measured by established renin assays.

The renin-angiotensin-aldosterone system in pre-eclampsia: the delicate balance between good and bad.

Pregnancy demands major changes of the cardiovascular system, and this involves, among others, activation of the RAAS (renin-angiotensin-aldosterone system), allowing an aldosterone-dependent increase in volume. Remarkably, a relative resistance to the pressor response of AngII (angiotensin II) develops simultaneously to prevent the increase in blood pressure that would normally accompany RAAS activation. The increase in volume, the degree of RAAS activation and the diminished pressor response to AngII are less pronounced in pre-eclampsia. However, animal models displaying excessive RAAS activation also result in a pre-eclampsia-like syndrome, and the aldosterone/renin ratio is elevated in pre-eclampsia compared with a normal pregnancy. New insights into the pathogenesis of pre-eclampsia have revealed a major role for VEGF (vascular endothelial growth factor), VEGF-inactivating sFlt-1 (soluble fms-like tyrosine kinase-1) and AT1 (angiotensin II type 1) receptor autoantibodies. The last mentioned activate AT(1) receptors, thereby potentially suppressing circulating renin and aldosterone. VEGF, both directly and indirectly (by increasing capillary density), affects adrenal aldosterone synthesis. The present review summarizes all of the recent findings regarding RAAS regulation in pre-eclampsia compared with normal pregnancy, concluding that factors such as sFlt-1 and AT(1) receptor autoantibodies disturb the delicate balance that normally results in a volume increase and a diminished vasoconstrictor response to AngII in pregnant women. It is possible that there are non-parallel changes in the circulating and renal RAAS in pre-eclampsia, which are potentially reflected by the urinary levels of renin.

New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin.

Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999-treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by ≥ 30% but did not unfold prorenin. Yet, it did bind to acid-activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999-induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.