Comparative assessment of CacyBP/SIP, ß-catenin and cannabinoid receptors in the adrenals of hypertensive rats.

Taking into account homeostatic disorders resulting from arterial hypertension and the key importance of CacyBP/SIP, ß-catenin and endocannabinoids in the functioning of many organs, it was decided to assess the presence and distribution of CacyBP/SIP, ß-catenin, CB1 and CB2 in the adrenal glands of hypertensive rats of various aetiology. The study was conducted on the adrenal glands of rats with spontaneous and renovascular hypertension. The expression of CacyBP/SIP, ß-catenin, CB1 and CB2 was detected by immunohistochemistry and real-time PCR method. The results of the present study revealed both lower gene expression and immunoreactivity of CacyBP/SIP in the adrenal glands of all hypertensive groups compared to the normotensive rats. This study demonstrated a reduction in the immunoreactivity and expression of the ß-catenin, CB1 and CB2 genes in the adrenals of 2K1C rats. While in SHR, the reaction showing ß-catenin and CB1 was very weak or negative, and the expression of CB2 in the adrenal glands of these rats increased. The results of this study show, for the first time, marked differences in the expression of CacyBP/SIP, ß-catenin and CB1 and CB2 cannabinoid receptors in the adrenal glands of rats with primary (SHR) and secondary hypertension (2K1C).

Apelin-13: a novel approach to suppressing renin production in RVHT.

Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.

Genetic Deletion of AT1a Receptor or Na+/H+ Exchanger 3 Selectively in the Proximal Tubules of the Kidney Attenuates Two-Kidney, One-Clip Goldblatt Hypertension in Mice.

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension.

Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension.

In malignant hypertension, far more severe kidney injury occurs than in the "benign" form of the disease. The role of high blood pressure and the renin-angiotensin-aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. KEY MESSAGES: The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.

Allisartan ameliorates vascular remodeling through regulation of voltage-gated potassium channels in hypertensive rats.

BACKGROUND: The objective of the present study was to determine the effect of allisartan, a new angiotensin II type 1 receptor antagonist on vascular remodeling through voltage gated potassium channels (Kv7) in hypertensive rats. METHODS: The study included a total of 47 Sprague Dawley (SD) rats. The animals were randomized to sham operation (n = 14), untreated hypertensive control group (n = 18) and allisartan treatment group (n = 15). Using renal artery stenosis, hypertension was induced in animals. Single dose of allisartan was administered intra-gastrically to animals in the allisartan treatment group and match placebo in the other 2 groups. Wire myography was used to measure the muscle tension in isolated mesenteric arteries from the animals. Real-time polymerase chain reaction was used to quantify the expression of Kv7 channel mRNA subunits. RESULTS: After 4 weeks of treatment, a significant decrease in mean arterial, systolic and diastolic blood pressure (SBP and DBP) was observed in allisartan treatment group compared to hypertension control group. The median arterial wall thickness and area/diameter ratio reduced significantly in treatment group compared to untreated hypertension group (P < 0.05). Wire myography demonstrated increased relaxation of mesenteric artery with increase in concentration of ML213. A significant up-regulation in the expression of all Kv7 mRNA subunits was observed in allisartan group compared to untreated hypertension group. CONCLUSIONS: From the results, allisartan was found to lower BP and preserve vascular remodeling through Kv7 channels.

Renovascular hypertension and RNF213 p.R4810K variant in Korean children with Moyamoya disease.

Moyamoya disease (MMD) is the most common underlying disease in Korean pediatric renovascular hypertension (RVH). The ring finger protein 213 (RNF213) p.R4810K variant is reported to be a pathologic variant in East Asian MMD. The purpose of this study was to evaluate hypertension (HTN) prevalence and clinical manifestations as well as RNF213 p.R4810K variant prevalence in Korean pediatric MMD patients. The medical records of pediatric MMD patients from January 2000 to June 2018 were retrospectively reviewed. RVH was confirmed by computer tomography angiography or renal Doppler ultrasonography. The American Academy of Pediatrics 2017 guideline for sex-, age-, and height-related blood pressure standards was used to define HTN. Of 706 patients with MMD, 40 (5.7%) had HTN. Among these patients, 22 had RVH and 12 had HTN with no evidence of renal artery stenosis (non-RVH). Patients with MMD and RVH had an MMD onset at a younger age and lower body mass index compared to those with MMD and non-RVH. Among the patients with MMD and HTN, 4 presented with HTN before developing MMD. Genetic testing for the RNF213 p.R4810K variant was performed in 32 patients with MMD and HTN. When the patient had a homozygous RNF213 p.R4810K variant, the odds ratio of RVH to non-RVH was 8.3. Our study suggests that RVH is more prevalent than non-RVH in pediatric MMD patients. Furthermore, RNF213 p.R4810K may be the cause of RVH in Korean children with MMD.

Nrf1 Knock-Down in the Hypothalamic Paraventricular Nucleus Alleviates Hypertension Through Intervention of Superoxide Production-Removal Balance and Mitochondrial Function.

Oxidative stress in the hypothalamic paraventricular nucleus (PVN) contributes greatly to the development of hypertension. The recombinant nuclear respiratory factor 1 (Nrf1) regulates the transcription of several genes related to mitochondrial respiratory chain function or antioxidant expression, and thus may be involved in the pathogenesis of hypertension. Here we show that in the two-kidney, one-clip (2K1C) hypertensive rats the transcription level of Nrf1 was elevated comparing to the normotensive controls. Knocking down of Nrf1 in the PVN of 2K1C rats can significantly reduce their blood pressure and level of plasma norepinephrine (NE). Analysis revealed significant reduction of superoxide production level in both whole cell and mitochondria, along with up-regulation of superoxide dismutase 1 (Cu/Zn-SOD), NAD(P)H: quinone oxidoreductase 1 (NQO1), thioredoxin-dependent peroxiredoxin 3 (Prdx3), cytochrome c (Cyt-c) and glutathione synthesis rate-limiting enzyme (glutamyl-cysteine ligase catalytic subunit (Gclc) and modifier subunit (Gclm)), and down-regulation of cytochrome c oxidase subunit VI c (Cox6c) transcription after Nrf1 knock-down. In addition, the reduced ATP production and elevated mitochondrial membrane potential in the PVN of 2K1C rats were reinstated with Nrf1 knock-down, together with restored expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (Tfam), coiled-coil myosin-like BCL2-interacting protein (Beclin1), and Mitofusin 1 (Mfn1), which are related to the mitochondrial biogenesis, fusion, and autophagy. Together, the results indicate that the PVN Nrf1 is associated with the development of 2K1C-induced hypertension, and Nrf1 knock-down in the PVN can alleviate hypertension through intervention of mitochondrial function and restorement of the production-removal balance of superoxide.

The Transcription Factor Sox6 Controls Renin Expression during Renal Artery Stenosis.

Background: Renal artery stenosis (RAStenosis) or renal artery occlusion is an intractable problem affecting about 6% of people >65 and up to 40% of people with coronary or peripheral vascular disease in the Unites States. The renal renin-angiotensin-aldosterone system plays a key role in RAStenosis, with renin (which is mainly produced in the kidney) being recognized as the driver of the disease. In this study, we will determine a new function for the transcription factor Sox6 in the control of renal renin during RAStenosis. Methods: We hypothesize that knocking out Sox6 in Ren1d-positive cells will protect mice against renovascular hypertension and kidney injury. To test our hypothesis, we used a new transgenic mouse model, Ren1dcre/Sox6fl/fl (Sox6 KO), in which Sox6 is knocked out in renin-expressing cells. We used a modified two-kidney, one-clip (2K1C) Goldblatt mouse model to induce RAStenosis and renovascular hypertension. BP was measured using the tail-cuff method. Renin, prorenin, Sox6, and NGAL expressions levels were measured with Western blot, in situ hybridization, and immunohistochemistry. Creatinine levels were measured using the colorimetric assay. Results: Systolic BP was significantly lower in Sox6 KO 2 weeks after RAStenosis compared with Sox6 WT (Ren1dcre/Sox6wt/wt). Renin, prorenin, and NGAL expression levels in the stenosed kidney were lower in Sox6 KO compared with Sox6 WT mice. Furthermore, creatinine clearance was preserved in Sox6 KO compared with Sox6 WT mice. Conclusions: Our data indicate that Sox6 controls renal renin and prorenin expression and, as such, has a function in renovascular hypertension induced by RAStenosis. These results point to a novel transcriptional regulatory network controlled by Sox6.

Genetics of renovascular hypertension in children.

OBJECTIVE: In most cases of renovascular hypertension in children, the cause is unclear. The aim of this study was to investigate genetic variation as a factor in the development of renovascular hypertension in children. METHODS: In a cohort of 37 unrelated children from a single tertiary referral center, exome sequencing was performed. We assessed variants in recognized and suspected disease genes and searched for novel ones with a gene-based variant-burden analysis. RESULTS: In the majority of patients, exome sequencing could not identify causative variants. We found a pathogenic variant in a recognized associated disease gene in five patients (three pathogenic variants in NF1, one in ELN and a deletion of chromosome 7q11.23, consistent with Williams syndrome). In two other patients, (likely) pathogenic variants were found in putative renovascular hypertension genes (SMAD6 and GLA), with clinical implications for both. Ten additional patients carried variants of uncertain significance (VUS) in known (n = 4) or putative (n = 6) renovascular hypertension disease genes. Rare variant burden analysis yielded no further candidate genes. CONCLUSION: Genetic contributors, such as germline mutations in NF1, ELN, 7q11.23del were present in only 5 out of 37 (14%) children with renovascular hypertension. Twelve other children (32%) had potentially causal variants identified, including a pathogenic variant in SMAD6; a vasculopathy gene hitherto unknown to link with renovascular hypertension. Most importantly, our data show that exome sequencing can rarely identify the cause of renovascular hypertension in nonsyndromic children. We suggest that nongenetic factors or somatic genetic variation will play a more important role.

Hemorrhagic stroke and renovascular hypertension with Grange syndrome arising from a novel pathogenic variant in YY1AP1.

Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke, contributing to rare but serious childhood morbidity and mortality. Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children. Grange syndrome (MIM#602531) is a rare disease characterized by multiple stenosis or occlusion of the renal, abdominal, coronary, and cerebral arteries, which can cause phenotypes of RVH and fibromuscular dysplasia (MIM#135580). We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes. At 1 year of age, she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. Chronic hypertension was observed, and abdominal computed tomography angiography showed characteristic bilateral renal artery stenosis. Whole-exome sequencing revealed a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). Biallelic YY1AP1 mutations are known to cause Grange syndrome. Unlike previously reported patients, our patient presented with intracerebral hemorrhagic stroke without anomalous brain artery or bone fragility. The phenotype in our patient may help better understand this ultra-rare syndrome. Grange syndrome should be considered in patients presenting with childhood-onset hypertension and/or hemorrhagic stroke for early clinical intervention.

Antioxidant and antihypertensive responses to oral nitrite involves activation of the Nrf2 pathway.

Impaired redox balance contributes to the cardiovascular alterations of hypertension and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may counteract these alterations. While nitrite recycles back to NO and exerts antioxidant and antihypertensive effects, the mechanisms involved in these responses are not fully understood. We hypothesized that nitrite treatment of two-kidney, one-clip (2K1C) hypertensive rats activates the Nrf2 pathway, promotes the transcription of antioxidant genes, and improves the vascular redox imbalance and dysfunction in this model. Two doses of oral nitrite were studied: 15 mg/kg and the sub-antihypertensive dose of 1 mg/kg. Nitrite 15 mg/kg (but not 1 mg/kg) decreased blood pressure and increased circulating plasma nitrite and nitrate. Both doses blunted hypertension-induced increases in mesenteric artery reactive oxygen species concentrations assessed by DHE technique and restored the impaired mesenteric artery responses to acetylcholine. While 2K1C hypertension decreased nuclear Nrf2 accumulation, both doses of nitrite increased nuclear Nrf2 accumulation and mRNA expression of Nrf2-regulated genes including superoxide dismutase-1 (SOD1), catalase (CAT), glutathione peroxidase (GPX), thioredoxin-1(TRDX-1) and -2 (TRDX-2). To further confirm nitrite-mediated antioxidant effects, we measured vascular SOD and GPX activity and we found that nitrite at 1 or 15 mg/kg increased the activity of both enzymes (P < 0.05). These results suggest that activation of the Nrf2 pathway promotes antioxidant effects of nitrite, which may improve the vascular dysfunction in hypertension, even when nitrite is given at a sub-antihypertensive dose. These findings may have many clinical implications, particularly in the therapy of hypertension and other cardiovascular diseases.

Long non-coding RNA cytoskeleton regulator RNA (CYTOR) modulates pathological cardiac hypertrophy through miR-155-mediated IKKi signaling.

Pathological cardiac hypertrophy, which may lead to heart failure and sudden death, can be affected by multiple factors. In our previous study, we revealed that IKKi deficiency induced cardiac hypertrophy through the activation of the AKT and NF-kB signaling pathway in response to aortic banding (AB). Non-coding RNAs, mainly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in normal developmental and pathological processes. In the present study, microarray analysis results from GEO database were analyzed, and upregulated lncRNAs in cardiac hypertrophy were identified. Of them, lncRNA cytoskeleton regulator RNA (CYTOR) obtained a fold-change of 6.16 and was positively correlated with IKBKE according to the data from The GTEx project. CYTOR knockdown significantly enhanced the inducible effect of AB operation on mice myocardial hypertrophy and Angiotensin II on cardiomyocyte hypertrophy. Moreover, miR-155 was significantly related to hypertrophic cardiomyopathy (HCM, |hsa05410) and predicted to target both CYTOR and IKBKE. Luciferase reporter and RIP assays revealed that CYTOR served as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE. Moreover, CYTOR knockdown reduced IKKi protein levels while activated NF-kB signaling pathway, whereas miR-155 inhibition exerted an opposing effect; the effect of CYTOR could be partially attenuated by miR-155 inhibition. Taken together, CYTOR might play a protective role in cardiac hypertrophy through miR-155 and downstream IKKi and NF-κB signaling, most possibly through serving as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE.

Nitrite treatment downregulates vascular MMP-2 activity and inhibits vascular remodeling in hypertension independently of its antihypertensive effects.

Hypertension is associated with cardiovascular remodeling. Given that impaired redox state activates matrix metalloproteinase (MMP)- 2 and promotes vascular remodeling, we hypothesized that nitrite treatment at a non-antihypertensive dose exerts antioxidant effects and attenuates both MMP-2 activation and vascular remodeling of hypertension. We examined the effects of oral sodium nitrite at antihypertensive (15 mg/kg) or non-antihypertensive (1 mg/kg) daily dose in hypertensive rats (two kidney, one clip; 2K1C model). Sham-operated and 2K1C hypertensive rats received vehicle or nitrite by gavage for four weeks. Systolic blood pressure decreased only in hypertensive rats treated with nitrite 15 mg/Kg/day. Both low and high nitrite doses decreased 2K1C-induced vascular remodeling assessed by measuring aortic cross-sectional area, media/lumen ratio, and number of vascular smooth muscle cells/aortic length. Both low and high nitrite doses decreased 2K1C-induced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay. Vascular MMP-2 expression and activity were assessed by gel zymography, Western blot, and in situ zymography increased with hypertension. While MMP-2 levels did not change in response to both doses of nitrite, both doses completely prevented hypertension-induced increases in vascular MMP activity. Moreover, incubation of aortas from hypertensive rats with nitrite at 1-20 µmol/L reduced gelatinolytic activity by 20-30%. This effect was fully inhibited by the xanthine oxidase (XOR) inhibitor febuxostat, suggesting XOR-mediated generation of nitric oxide (NO) from nitrite as a mechanism explaining the responses to nitrite. In vitro incubation of aortic extracts with nitrite 20 µmol/L did not affect MMP-2 activity. These results show that nitrite reverses the vascular structural alterations of hypertension, independently of anti-hypertensive effects. This response is mediated, at least in part, by XOR and is attributable to antioxidant effects of nitrite blunting vascular MMP-2 activation. Our findings suggest nitrite therapy to reverse structural alterations of hypertension.

A postzygotic KRAS mutation in a patient with Schimmelpenning syndrome presenting with lipomatosis, renovascular hypertension, and diabetes mellitus.

Schimmelpenning syndrome is a rare neurocutaneous disorder categorized as a mosaic RASopathy due to postzygotic HRAS or KRAS mutations. We report a 6-year-old girl diagnosed with Schimmelpenning syndrome due to a postzygotic KRAS G12D mutation. The patient had three atypical symptoms of Schimmelpenning syndrome: renovascular hypertension, congenital lipomatosis, and diabetes mellitus. The first two symptoms may overlap with phenotypes of other neurocutaneous syndromes or congenital lipomatous overgrowth syndrome due to mosaic RASopathies or other somatic mosaic mutations. We propose that impaired glucose tolerance was caused by KRAS mutation and a novel clinical phenotype of Schimmelpenning syndrome. Our study indicated that clinical diagnosis of Schimmelpenning syndrome or related conditions should be reorganized with genetic diagnosis of postzygotic mutation. Moreover, further accumulation of genetically proven cases with mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular-targeted therapy.

Boldine Improves Kidney Damage in the Goldblatt 2K1C Model Avoiding the Increase in TGF-ß.

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.

Renovascular hypertension associated with JAK2 V617F positive myeloproliferative neoplasms treated with angioplasty: 2 cases and literature review.

Myeloproliferative neoplasms (MPNs) with Janus kinase 2 (JAK2) mutation are associated with a high risk for occlusive vascular diseases. We report 2 cases of renovascular hypertension associated with JAK2 V617F mutation-positive MPNs and provide a literature review. In Case 1, a 63-year-old woman had resistant hypertension, massive proteinuria, and erythrocytosis. Evaluations revealed right renal artery stenosis causing renovascular hypertension and polycythemia vera with JAK2 V617F mutation. Renin-angiotensin system inhibitors and subsequent angioplasty controlled the blood pressure and the proteinuria resolved. In Case 2, a 74-year-old woman had resistant hypertension and thrombocytosis. Evaluations confirmed left renal artery stenosis and essential thrombocythemia with JAK2 V617F. Angioplasty cured the hypertension. A literature review of 18 cases revealed the following as the most common characteristics of MPN-associated renovascular hypertension: manifests primarily in women; is associated with untreated polycythemia vera and essential thrombocythemia, concomitant leukocytosis, and JAK2 mutation positivity; and is responsive to angioplasty. This report demonstrates that JAK2 mutation-positive MPNs are a less common but important underlying cause of adult renovascular hypertension.

Dynamics of Distribution of Capillaries with Matrix Metalloproteinase-2 and Its Tissue Inhibitor in Rat Brain during Development of Experimental Hypertension.

The capillaries containing MMP-2 and its tissue inhibitor TIMP-2 were examined in cerebral cortex and white matter obtained from intact Wistar rats (n=5) and the rats with progressing experimental renovascular hypertension (n=35). In hypertensive rats, the changes in intensity of the immunohistochemical reaction and in the density of capillaries expressing TIMP-2 significantly differed from the corresponding values in MMP-2-positive capillaries, which resulted in pronounced deviation of MMP-2/TIMP-2 index from the control level (especially in cerebral cortex) probably attesting to enhanced risk of complications in cases with arterial hypertension.