bluuebunny/crossref_metadata_2025 huggingface dataset:
The What, the Why, and the How of Liver Ablations: A Practical Guide for the Medical Oncologist
Authors: Gennaro Nicolò , Schiaffino Simone , Mauri Giovanni , Monfardini Lorenzo
Published: August 2021

Interventional oncology plays a major role within modern oncological patient management. Image-guided thermal ablation has been recognized as a successful local therapeutic option in patients with primary and secondary malignant liver diseases, as also recalled by the recent European Society of Medical Oncology (ESMO) guidelines on colorectal metastases. As image-guided treatments may be as effective as surgery in selected patients with liver lesions, the clinical oncologist should be familiar with the indications, risks, and technical aspects of liver ablation in order to provide their patients with the best outcomes. This article provides a broad overview of the most commonly used ablation techniques and highlights the most relevant technical aspects such as the ideal setting in the operating theatre; which image-guided methods are available, including the growing application of fusion imaging; or contrast-enhanced ultrasound for guiding/monitoring the procedure. A further aim is to expand the knowledge among medical oncologists about liver ablation procedures and to provide insights into the future perspectives of percutaneous minimally invasive procedures in the liver.
Abstract 07: Collecting Duct (Pro) Renin Receptor(PRR) Promotes Kidney Fibrosis Via Macrophage Alternative Activation Mediated By Soluble PRR (sPRR)-Dependent Activation Of Yap/Taz Axis
Authors: Feng Ye , Xie Shiying , Luo Renfei , Wang Fei , Yang Tianxin
Published: August 2021

Renal collecting duct (CD), an important site for fine-tuning urinary Na
+
and water excretion, is not traditionally thought to play a role in pathogenesis of chronic kidney disease. In the present study, we examined a profibrotic role of CD PRR in a mouse model of unilateral ureteral obstruction (UUO) and further defined the underlying mechanism involving soluble PRR (sPRR)-dependent activation of alternative macrophages activation. We subjected mice with CD-specific deletion of PRR (CD PRR KO) and their floxed controls to UUO or sham surgery. After 7 days of UUO, CD PRR KO decreased the fibronectin (28.6±6.8%) and α-SMA (39.2±7.8%) protein expression in obstructed kidneys. The Masson’s trichrome staining data also showed that CD PRR KO significantly attenuated UUO-induced collagen deposition and histological damage in the kidney. In parallel, CD PRR KO reduced
TGF-β1
(56.7±3.2%) and
TGF-β2
(53±1.2%) mRNA expression in obstructed kidneys. Moreover, in macrophages sorted from obstructed kidneys of CD PRR KO mice showed a significantly reduced of M2 macrophage markers such as mannose receptor (
MR
) (58.7±2.1%), arginase-1 (
Arg-1
) (50±1.5%), chitinase-like lectins (
YM-1
) (59.3±1.9%), inflammatory zone-1 (
Fizz1
) (39.1±4.1%) mRNA expression and Yes-associated protein (
Yap
) (77±6.8%)/ transcriptional coactivator with PDZ-binding motif (
Taz
) (54.5±1.8%) mRNA expression compared with macrophages sorted from obstructed kidneys of floxed mice. Meanwhile, plasma sPRR was elevated in floxed mice by UUO and this elevation was blunted by CD PRR KO (23.7±0.4%). Administration of site-1 protease (S1P) inhibitor PF-429242 to C57BL/6 mice with UUO almost completely recapitulated the antifibrotic action as well as the inhibitory effect on M2 activation of CD PRR KO. In bone marrow-derived macrophages, sPRR-His treatment promoted macrophage M2 polarization, fibrosis and Yap/Taz expression. Overall, these results suggest that activation of CD PRR releases sPRR that activates M2 polarization via Yap/Taz axis, leading to renal fibrosis during UUO.
Abstract 08: Functional Characterisation Of Uromodulin Promoter Risk Variants Associated With Blood Pressure
Authors: Fisher Simon , Graham Lesley , Graham Delyth , McBride Martin
Published: August 2021

Using a genome wide association study (GWAS), we identified a locus on the promoter of the human uromodulin (UMOD) gene associating with primary hypertension. In this study we aimed to identify genotype-differential protein binding partners which influence UMOD expression and to examine pathways linking UMOD expression to blood pressure variability in humans.We examined a variant on this locus, by incubating 50mer oligonucleotides featuring alternate alleles (C/G) with HEK-293 nuclear protein extract. Subsequently, we performed an electrophoretic mobility shift assay (EMSA) and purified protein complexes to analyse by Tandem-mass-spectroscopy (MS2). Filtering for peptide matches >20, we interpreted these data by Ingenuity Pathway Analysis (IPA). From a bank of 98 human renal biopsy samples, we assessed UMOD expression by qRT-PCR. RNA-seq was performed using the NextSeq-500 system on a subset of high and low UMOD expressors (n=3/ group). Differentially expressed (false-discovery-rate (FDR) <0.05) genes were identified, with strong correlations in these data validated by qRT-PCR. Implicated pathways were interpreted using both IPA and gene set enrichment analysis (GSEA).The C allele at our risk variant displayed greater binding affinity versus the G allele; 0.77 (0.13, 1.40, 95%CI). In contrast no difference in binding affinity was observed between the T and C alleles of our control variant, 0.08 ( -1.22, 1.39, 95%CI). Mass spectroscopy of EMSA complexes identified PARP1 binding at this target. By IPA we identified a complex between PARP1 and HNF1β as driving expression of UMOD. RNA-sequencing identified positive correlation in expression of UMOD and the Na-K-Cl cotransporter (NKCC2) (FDR=2.58e-9, log2-fold-change [L2FC]= 3.3), the renal outer medullary potassium channel (ROMK) (FDR=3.69e-2, L2FC= 2.79) and the epithelial sodium channel (ENaC) (FDR=1.83e-2, L2FC= 1.25). We validated this coexpression between UMOD and NKCC2 by qRT-PCR and show a significant correlation (p=2.2e-16, R2= 0.844, n=84).Together these data suggest our risk variant contributes to differences in UMOD expression via a PARP1:HNF1β transcriptional complex and these differences associate with blood pressure through sodium homeostasis in the human kidney.
Abstract 10: MANP Activation of the Cyclic GMP/PDE2/CYP11B2 Pathway Inhibits Aldosterone In Vitro and In Vivo
Authors: Chen Yang , Iyer Seethalakshmi R , Nikolaev Viacheslav , Naro Fabio , Pellegrini Manuela , Lee Hon-chi , Burnett John C
Published: August 2021

Aldosterone is a critical driver for cardiovascular disease (CVD). We recently discovered that MANP, a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP. MANP is currently entering clinical trials for hypertension and thus understanding its aldosterone suppressing mechanism is important. The mechanism of aldosterone inhibition by natriuretic peptides (NPs) remains to be clearly defined. Conflicting results were reported on the roles of particulate guanylyl cyclase A receptor (pGC-A) and NP clearance receptor (NPRC) in aldosterone inhibition. Furthermore, the functions of protein kinase G (PKG) and phosphodiesterases (PDE) on aldosterone regulation are not clear. Herein, we investigated the molecular mechanism of aldosterone regulation in the human adrenocortical cell line H295R and in mice. We firstly showed that pGC-A mediates aldosterone inhibition. In contrast, with NPRC agonist and antagonist, we showed that NPRC did not inhibit aldosterone. Next, we confirmed that MANP inhibits aldosterone via PDE2, not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer (FRET) experiments. Specifically, MANP suppressed ANGII mediated activation of aldosterone (fold change) MANP+ANGII 3.2±0.1* vs. ANGII 3.8±0.1 (*p<0.05) with IBMX, a PDEs inhibitor and the PDE2 antagonist Bay 60-7550 reversed MANP-mediated aldosterone suppression (IBMX+MANP+ANGII 3.9±0.2 and Bay+MANP+ANGII 4.1±0.1). With PKG agonists and inhibitors, aldosterone levels were not changed. In PDE2 activity FRET studies, aldosterone control was 3.7±0.4 and with MANP 0.9±0.2* supporting PDE2 activation by MANP. Further, the inhibitory effect of PDE2 is mediated by a reduction of intracellular Ca2+ concentration (~22%). We then showed that MANP directly reduced aldosterone synthase CYP11B2 expression in vitro. Lastly, in PDE2 knockout mice (embryonic lethal), embryonic adrenal CYP11B2 expression is markedly increased (wild type: 1±0.2, KO: 2.8±0.5*). Our findings innovatively elucidate the pGC-A/cGMP/PDE2 pathway in aldosterone inhibition by MANP in vitro and in vivo. Additionally, our data also support the development of MANP as a novel ANP analog drug for CVD.
Abstract 15: The Cardio-renal Effects Of Il-33 Treatment In Myocardial Infarction-induced Kidney Damage
Authors: Amin Ghadir , Habeichi Nada , Ghali Rana , Booz George W , Mallat Ziad , Zouein Fouad A
Published: August 2021

Introduction:
Interleukin (IL)-33 is a nuclear alarmin released upon tissue damage and initiating a signaling cascade by binding to its cell membrane receptor ST2. Accumulating evidence shows that the IL-33/ST2 axis mediates both inflammatory and repair responses in different models of kidney diseases, suggesting a Janus-like effect that varies within disease context and progression. This study aimed to investigate the effect of IL-33 administration on acute kidney damage at 4 and 7 days post-MI in mice.

Methods:
MI was induced by ligating the left anterior descending coronary artery, followed by IL-33 (1μg/day)/vehicle (PBS) treatment for 4 and 7 consecutive days. Cardiac systolic function was assessed, and kidneys were subjected to histological and molecular analysis.

Results:
IL-33 had no significant effect on cardiac hemodynamic parameters at 4 days but significantly decreased the left ventricular ejection fraction (20 ± 1 vs 9.8 ± 2, P<0.01) at 7 days post-MI. In the kidneys, reduced glomerular retraction (0.57 ± 0.09 vs 0.24 ± 0.06, P < 0.05) was observed at day 4 post-MI only, along with a decrease in the protein expression of αSMA (2.89 ± 0.33 vs 0.43 ± 0.13, P < 0.001) and collagen 3 (1.96 ± 0.78 vs 0.34 ± 0.14, P < 0.05). Conversely, increased protein levels of αSMA (0.86 ± 0.42 vs 21.5 ± 2.53, P < 0.0001) and collagen 3 (0.33 ± 0.08 vs 1.71 ± 0.22, P<0.01) were observed at day 7 post-MI. Total renal fibrosis increased to levels comparable to the MI vehicle group at day 4 and 7 post-MI. The mRNA expression of the apoptotic BAX/BCL2 ratio (1.05 ± 0.09 vs 0.36 ± 0.23, P < 0.05) decreased only at day 4 post-MI, whereas an increase in the mRNA levels of the DNA repair enzyme PARP-1 (1.37 ± 0.06 vs 2.05 ± 0.4, P<0.05) was observed at day 7 post-MI. A marked increase in the mRNA expression of Sirtuin 3 (1.87 ± 0.57 vs 11.72 ± 4.24, P < 0.05) and in total renal NAD levels (386.75 ± 40.52 vs 706.36 ± 66.09, P < 0.05) was observed at day 4 post-MI.

Conclusion:
Collectively, our findings suggest that although IL-33 treatment improves renal homeostasis 4 days post-MI, this protection is offset by day 7 post-MI through enhanced renal morphological and molecular alterations. The observed renal deterioration between day 4 and day 7 post-MI correlate with aggravated cardiac dysfunction.
Abstract 21: Sex Differences In Circadian Blood Pressure
Authors: Visniauskas Bruna , Ogola Benard O , Kilanowski-doroh Isabella , Harris Nicholas R , Diaz Zaidmara T , Lindsey Sarah H
Published: August 2021

Hypertensive patients frequently show a lack of 10% decline in nighttime (or nondipping) blood pressure (BP), which is a strong predictor of a cardiovascular event. Clock genes are essential regulators in diurnal BP in the vasculature during hypertension. However, little is known if vascular circadian clock factors influence BP rhythms in a sex-dependent manner. To test the hypothesis that AngII-induced hypertension disrupts the expression pattern of peripheral clock genes, male and female C57Bl/6J mice were subjected to AngII (700 ng/kg/min) infusion for two weeks. BP was measured by radiotelemetry (N=7/group). After two weeks, the animals were sacrificed during daytime or nighttime, and aortas were assessed for expression of clock genes (Per1, Per2, Bmal1) and estrogen receptors (ERα and GPER). Two-way ANOVA was used to compare light-dark cycle and AngII treatment effects. Hypertensive females (MAP: day 121 ± 9 vs. night 126 ± 10 mmHg, P=0.39; 7.3% dipping) but not males (MAP: day 128 ± 3 vs. night 140 ± 2 mmHg, P=0.01; >10% dipping) developed a non-dipping phenotype. AngII-hypertension amplified the circadian pattern of Per1 in the male aorta but removed the Per1 circadian variation in the female aorta. AngII did not alter Per2 oscillation in the aorta of either sex. Bmal1 patterns were also amplified in males and reversed in females. In response to AngII, aortic ERα expression was augmented during the day in females (control 287 ± 14 vs. AngII 413 ± 42 copies/ng RNA; P=0.01) but not in males (P=0.34). Furthermore, GPER expression exhibited a circadian oscillation in control (day 9 ± 1 vs. night 20 ± 7.6 copies/RNA ng) and hypertensive males (day 12 ± 17 vs. night 20 ± 5 copies/RNA ng, P=0.04), but not in females. In conclusion, sex differences exist in non-dipping BP patterns and circadian disruption of estrogen receptors and clock genes Per1 and Bmal1 in the vasculature after AngII treatment. This data suggest that females may be more vulnerable to circadian disruption during hypertension.
Abstract 28: Omeprazole Administration To Women With Preterm Preeclampsia: Effects On Circulating Soluble Fms-like Tyrosine Kinase-1, Placental Growth Factor And Endothelin-1 Secretion.
Authors: Neuman Rugina I , Visser Willy , Danser Jan H
Published: August 2021

Low soluble Fms-like tyrosine kinase (sFlt-1) has been reported in women with suspected or confirmed preeclampsia (PE) coincidentally using proton pump inhibitors (PPIs), suggesting a role for these agents as potential treatment for PE. Here, we examined whether administration of omeprazole to women with PE could acutely reduce their circulating levels of sFlt-1 or enhance their placental growth factor (PlGF) concentrations. We performed a randomized controlled trial in which women (≥ 18 years) with confirmed preeclampsia and a gestational age between 20
+0
and 34
+6
weeks were allocated to receive 40mg omeprazole once daily or no omeprazole. Blood was collected at baseline and days 1,2,4,8 followed by twice-weekly until delivery. Primary outcome was specified as the difference in sFlt-1 or PlGF 4 days after omeprazole initiation compared to the non-omeprazole group. Secondary outcomes were defined as between-group differences in longitudinal course of sFlt-1 and PlGF and pregnancy outcomes. Between Dec 2018 and June 2021, 50 women with PE were randomized, of which 40 women remained pregnant after 4 days. Mean maternal age was 30 years, and median gestational age was 31 weeks. Baseline sFlt-1 levels did not differ between non-omeprazole (n=20) and omeprazole group (n=20) (10743 vs. 7110pg/mL, p=0.11), neither did the levels of PlGF (p=0.14). After 4 days, sFlt-1 levels remained similar in women receiving omeprazole compared to women not receiving omeprazole (8364 vs. 13017pg/mL, p=0.14), and the same was true for PlGF (90 vs. 55pg/mL, p=0.14). Using linear mixed models, no difference in longitudinal course of sFlt-1 or PlGF could be attributed to the treatment group, when adjusted for baseline values and GA at enrollment (p=0.47). Women receiving omeprazole had a similar length of pregnancy compared with those not receiving this drug (median 15 vs. 14 days, p=0.70). Except for a higher neonatal intubation rate in the non-omeprazole group (31% vs 4%, p=0.02) there were no differences in maternal/perinatal complications between the two groups. Our findings suggest that daily administration of 40mg in women with PE do not alter their circulating levels of sFlt-1 and PlGF, arguing against a role for this drug as a potential treatment for this syndrome.
Abstract 32: Exercise Training Corrects Blood-brain Barrier Dysfunction Within Preautonomic Areas Of Spontaneously Hypertensive Rats By Normalizing The Augmented Transcytosis
Authors: Candido Vanessa B , Ceroni Alexandre , Colquhoun Alison , Michelini Lisete C
Published: August 2021

Introduction:
Besides intense neuro-hormonal activation, hypertension is accompanied by blood-brain barrier (BBB) dysfunction within preautonomic areas and marked autonomic imbalance. We showed previously that exercise training (T) corrected both increased BBB leakage and autonomic dysfunction. There is no information on the mechanism(s) conditioning the normalization of BBB function

Hypothesis:
We hypothesized that T could modify the transcytosis and/or the paracellular transport across the capillary endothelium

Methods:
SHR and Wistar rats allocated to T (55% maximal capacity) or sedentary (S) protocols were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (fluorescent Rhodamine-70kDa+FITC-10kDa dyes given
ia
). To analyze hypertension- and T-induced BBB changes, paraventricular hypothalamic nuclei (PVN) was harvested and processed for immunofluorescence and transmission electron microscopy

Results:
SHR-S
vs
Wistar-S exhibited augmented SAP and reduced pulse interval (PI) variability, decreased spontaneous baroreflex sensitivity (BrS), increased both PVN BBB leakage (11.4±0.6
vs
3.48 %area) and transcytosis (8.1±1.2
vs
4.8±0.8 vesicles/capillary) but no change in tight junctions’expression (TJ, number/capillary). SHR-T showed a near normal autonomic control, resting bradycardia and a partial AP reduction (-9%) accompanied by normalization of both BBB leakage (3.6±1.5 %area) and transcytosis (3.8±0.7 vesicles/capillary), and increased TJs’ extension (60% occupancy of capillary borders) without changing its expression. Hypertension- and T-induced transcytosis changes were confirmed by caveolin-1 immunofluorescence (SHR-S=139±11, Wistar-S=86±8, SHR-T=81±6 arbitrary units). There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=1.77x -3.46, r
2
=0.722, P<0.001) and BBB leakage x SAP variability (Y=2.30x +16.6, r
2
=0.246, P<0.001)

Conclusions:
PVN BBB dysfunction in hypertension is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates SHR’s autonomic control by normalizing transcytosis, with an additional TJs structure improvement
Abstract 33: Impaired Mitochondrial Metabolism Contributes To Endothelial Dysfunction And Hypertension Independently From Oxidative Stress
Authors: Dikalova Anna , Tkachuk Liliya , Vafina Svetlana , Dikalov Sergey
Published: August 2021

Metabolic disorders contribute to pathogenesis of endothelial dysfunction, and mitochondrial deacetylase Sirt3 is critical in regulation of metabolic and antioxidant functions, but the role of Sirt3 has been largely ignored. We have recently shown that Sirt3 level is reduced in human hypertension. We propose Sirt3 as a novel target to improve the treatment of endothelial dysfunction and hypertension. Oxidative stress promotes metabolic dysregulation while metabolic conditions increase production of reactive oxygen species. In this work we have discerned the pathological role of impaired mitochondrial metabolism and oxidative stress using our new SOD2K68R deacetylation mimic mouse model. SOD2K68R mice are protected from oxidative stress because mutation of lysine 68 to arginine prevents SOD2 inactivation by acetylation. To define the specific role of impaired mitochondrial metabolism in endothelial dysfunction and hypertension, we have crossed SOD2K68R with Sirt3
-/-
mice. Resultant SOD2K68R-Sirt3
-/-
mice are protected from mitochondrial oxidative stress but have impaired Sirt3-mediated mitochondrial metabolism. We have tested the hypothesis that impaired Sirt3-mediated mitochondrial metabolism in SOD2K68R-Sirt3
-/-
mice promotes vascular dysfunction and hypertension. SOD2K68R-Sirt3
-/-
mice are protected from AngII-induced superoxide measured by mitoSOX and DHE. Meanwhile, systolic blood pressure in AngII-infused SOD2K68R-Sirt3
-/-
mice was substantially higher than in SOD2K68R mice but lower than in Sirt3
-/-
mice. To define the role of mitochondrial metabolism in vascular homeostasis we analyzed metabolic, inflammatory, and cellular pathways. LCAD hyperacetylation and increased HIF1α in SOD2K68R-Sirt3
-/-
mice indicates impaired mitochondrial fatty acid oxidation and increased glycolysis which were further exacerbated by AngII-infusion and NFkB/ICAM increase promoting vascular inflammation. The loss of VeCAD in SOD2K68R-Sirt3
-/-
Sham mice was further aggravated in AngII-infusion supporting alteration of endothelial phenotype in SOD2K68R-Sirt3
-/-
mice. These data indicate that impaired mitochondrial metabolism contributes to endothelial dysfunction and hypertension independently from oxidative stress.
Abstract 40: SARS-CoV-2/ACE2 Induces Vascular Inflammatory Responses In Human Microvascular Endothelial Cells Independently Of Viral Replication
Authors: Montezano Augusto C , Camargo Livia , Mary Sheon , Neves Karla B , Rios Francisco J , Alves-lopes Rheure , Beattie Wendy , Herbert Imogen , Herder Vanessa , Szemiel Agnieszka M , McFarlane Steven , Palmarini Massimo , Bhella David , Touyz Rhian M
Published: August 2021

SARS-CoV-2, the virus responsible for COVID19, binds to ACE2, via its spike protein S1 subunit, leading to viral infection and respiratory disease. COVID-19 is associated with cardiovascular disease and systemic inflammation. Since ACE2 is expressed in vascular cells we questioned whether SARS-CoV-2 induces vascular inflammation and whether this is related to viral infection. Human microvascular endothelial cells (EC) were exposed to recombinant S1p (rS1p) 0.66 μg/mL for 10 min, 5h and 24h. Gene expression was assessed by RT-PCR and levels of IL6 and MCP1, as well as ACE2 activity, were assessed by ELISA. Expression of ICAM1 and PAI1 was assessed by immunoblotting. ACE2 activity was blocked by MLN4760 (ACE2 inhibitor) and siRNA. Viral infection was assessed by exposing Vero E6 (kidney epithelial cells; pos ctl) and EC to 10
5
pfu of SARS-CoV-2 where virus titre was measured by plaque assay. Co-IP coupled mass spectrometry protein identification and label free proteomics were used to investigate ACE2-mediated signalling. rS1p increased IL6 mRNA (14.2±2.1
vs.
C:0.61±0.03 2^-ddCT) and levels (1221.2±18.3
vs.
C:22.77±3.2 pg/mL); MCP1 mRNA (5.55±0.62
vs.
C:0.65±0.04 2^-ddCT) and levels (1110±13.33
vs.
C:876.9±33.4 pg/mL); ICAM1 (17.7±3.1
vs.
C:3.9±0.4 AU) and PAI1 (5.6±0.7
vs.
C: 2.9±0.2), p<0.05. MLN4760, but not rS1p, decreased ACE2 activity (367.4±18
vs.
C: 1011±268 RFU, p<0.05) and blocked rS1p effects on ICAM1 and PAI1. ACE2 siRNA blocked rS1p-induced IL6 release, ICAM1, and PAI1 responses as well as rS1p-induced NFκB activation. Proteomics analysis of the global effect of rS1, identified biological process enrichment of proteins from virus transcription and NFκB signalling. ACE2 Co-IP identified 216 interacting proteins (filtered with ≥1 unique peptide, 1% FDR), linked to cytokine production and inflammation. EC were not susceptible to SARS-CoV-2 infection, while the virus replicated well in Vero E6. In conclusion, we demonstrate that rS1p induces an inflammatory response through ACE2 in endothelial cells. These effects seem to be independent of viral infection. Our findings suggest that vascular inflammation in COVID-19 involves activation of ACE2-mediated pro-inflammatory signalling that may be unrelated to viral replication.
Abstract 41: Changes In Renal Oxygen Consumption With High-salt Diet Differ Between Sprague Dawley And Dahl Salt Sensitive Rats.
Authors: Shimada Satoshi , Dash Ranjan K , Cowley Allen W
Published: August 2021

It has appeared evident that blood flow to the renal cortex which is required for glomerular filtration far exceeds the delivery of O
2
required for tubular metabolic needs. Yet, the metabolic needs of kidneys are second only to the heart per gram tissue and changes in O
2
extraction and utilization have not been directly measured in face of enhanced workloads such those imposed by high salt (HS) diets. We have developed techniques enabling continuous 24 hr/d monitoring of renal blood flow (RBF; Transonic flow probe) together with blood pressure (BP, 24hr/d) and intermittent sampling of arterial and renal venous blood over 21 days. O
2
content (mL/dL) was determined as 1.31 х Hemoglobin (Hb) (g/dL) х HbO
2
(%) + 0.003 х PaO
2
(mmHg); O
2
consumption (ml/min) was determined as RBF (ml/min) х (arterial-renal venous O
2
content difference). Sprague Dawley rats (SD; n=7; 10 wk age) were compared to Dahl salt-sensitive (SS; n=6; 8 wk age) rats fed 0.4% NaCl and during the 21 days of 4.0% NaCl (HS) diet. Beginning 7 days following surgery, RBF and BP were recorded 24 hr/day, and arterial and renal venous blood sampled for determination of blood gases (ABL800 FLEX radiometer) at 7, 14 and 21 of the HS diet. Average 24 hr mean BP of SD rats increased with the HS diet from 111±2 to 119±5 mmHg and SS rats rose from 121±5 to 155±9 mmHg (p<0.05); average 24 hr RBF of SD rats rose from 9.2±0.6 to 11.7
+
0.6 ml/min (p<0.05) while SS rats exhibited little change (7.0±0.6 to 7.0
+
0.9). RBF when expressed per gram kidney weight (gkw; determined in separate groups of rats) remained unchanged in both SD and SS rats in response to the HS diet. SS rats exhibited lower levels of RBF gkw than SD rats (p<0.05). Expressed either as absolute values or gkw, O
2
extraction and consumption was increased significantly in SD rats but not SS rats fed the HS diet. The results of the study indicate that despite high levels of RBF per tissue weight, increased metabolic work imposed by a HS diet resulted in a significant increase of RBF, O
2
extraction and consumption in normal rats. In contrast, SS rats exhibited lower levels of RBF but failed to increase either O
2
delivery or extraction. This failure may contribute importantly to altered metabolic substrate utilization in SS rats fed a HS diet, progression of ischemic related injury and hypertension.
Abstract 42: Inhibiting Stimulatory Dendritic Cells Reduces Early Progressive Proteinuria In Obese Dahl Salt-sensitive Rats.
Authors: Ekperikpe Ubong S , Shields Corbin , Brown Andrea K , Poudel Bibek , Cornelius Denise C , Williams Jan M
Published: August 2021

Childhood/prepubertal (PPO) obesity has emerged as an epidemic and major health problem over the last few decades and is a risk factor for the development of proteinuria. With the rising prevalence of obesity in children, studies examining how obesity contributes to the early development of proteinuria and renal injury in children are lacking. Recently, we observed that the early progression of proteinuria in the obese SS
LepR
mutant rats was associated with the increased renal infiltration of stimulatory dendritic cells (sDCs). Previous studies have demonstrated that sDCs interact with and activate T-cells to elicit a pro-inflammatory response. Therefore, the current study examined whether chronic treatment with abatacept will reduce proteinuria in SS
LepR
mutant rats prior to puberty by interfering with sDC-T-cell crosstalk. Four-week-old SS and SS
LepR
mutant rats were treated with either vehicle (PBS) or abatacept (1 mg/kg, i.p. every alternate day) for 4 weeks. We observed no significant differences in blood glucose levels and mean arterial pressure between vehicle- and abatacept-treated SS and SS
LepR
mutant rats. While proteinuria only rose from 9±3 to 48±28 mg/day in SS rats, proteinuria markedly increased from 40±13 to 638±73 mg/day in SS
LepR
mutant rats. Chronic treatment with abatacept significantly decreased the progression of proteinuria by almost 50% in SS
LepR
mutant rats (350±15 mg/day; p<0.05 vs. vehicle-treated SS
LepR
mutant rats) without having any effect in SS rats (29±11 mg/day). We observed a significant increase in the renal infiltration of sDCs and cytotoxic T-cells in SS
LepR
mutant rats in comparison to their lean SS counterparts, and chronic treatment with abatacept reduced the infiltration of sDCs and cytotoxic T-cells only in the SS
LepR
mutant rats. These data indicate that targeting sDC/T-cell interaction pathways could offer novel therapeutic insights in the early management of proteinuria and renal injury associated with PPO.
Abstract 43: Non-Canonical AT1R/b-Arrestin2 Activation In Brain As A Regulator Of Fluid Homeostasis And Blood Pressure
Authors: Mathieu Natalia M , Nakagawa Pablo , Brozoski Daniel , Grobe Justin L , Sigmund Curt D
Published: August 2021

The brain renin angiotensin system (RAS) is known for its role in cardiovascular and metabolic regulation. Angiotensin II (Ang II) is the major active product of the RAS, exerting most of its physiological effects through the angiotensin type-1 receptor (AT
1
R). Canonical or G-protein-mediated signaling of the AT
1
R within the brain has long been known to induce a dipsogenic and pressor response upon Ang II stimulation. Non-canonical or β-Arrestin mediated signaling is thought to counterbalance the detrimental effects of canonical signaling. However, the non-canonical AT
1
R/β-Arrestin pathway within the brain is understudied. Therefore, it is hypothesized that β-Arrestin activation contributes to fluid homeostasis and blood pressure (BP) regulation. Global β-Arrestin1 (
Arrb
1) and β-Arrestin2 (
Arrb
2) knockout (KO) mice were employed to evaluate drinking behavior and BP with and without deoxycorticosterone acetate (DOCA). Age- and sex-matched C57BL/6J mice served as controls. Mice were subjected to the two-bottle choice paradigm, in which the animals were presented with two bottles, one containing water and one containing 0.15M saline. In the absence of DOCA, mice lacking β-Arrestin2 had increased saline intake when compared to β-Arrestin1-KO and wildtype (WT=2.2±0.2 and
Arrb
1-KO=2±0.4 vs
Arrb
2-KO=5±0.7 mL/day; p<0.001; n=13, 11 and 9, respectively). This resulted in a saline preference, which means mice preferred saline over water by more than 50% by volume. In the presence of DOCA, mice lacking β-Arrestin2 had increased saline intake when compared to β-Arrestin1-KO and wildtype (WT=10.6±1.2 and
Arrb
1-KO=6.5±0.8 vs
Arrb
2-KO=16.6±2 mL/day; p<0.001; n=13, 11 and 9, respectively). However, these mice did not develop a saline preference. Preliminarily, β-Arrestin2-KO mice exhibited higher BP when compared to WT at baseline (WT=108±5 vs
Arrb
2-KO=124±6 mmHg; n=2), which was exacerbated in response to DOCA (WT=122±6 vs
Arrb
2-KO=140±5 mmHg; n=2). These findings suggest that β-Arrestin2 might counterbalance effects of canonical activation of the AT
1
R through G proteins. Overall, β-Arrestin2 appears to protect against cardiovascular diseases since the genetic ablation of β-Arrestin2 resulted in an increase in saline intake and exacerbated BP.
Abstract 44: VEGF Inhibitor-induced Vascular Dysfunction Is Ameliorated By PARP/TRPM2 Inhibition
Authors: Neves Karla B , Alves-lopes Rheure , Lang Ninian , Montezano Augusto C , Touyz Rhian M
Published: August 2021

Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi), which are used as anti-angiogenic drugs in cancer treatment. Clinical observations suggest that the combination of VEGFi with another anti-cancer drug, olaparib (PARP inhibitor [PARPi]), may attenuate the development of hypertension. However putative vascular mechanisms are unknown. PARP plays a major role in the activation of TRPM2, a redox-sensitive Ca
2+
channel, which is associated with hypertension-induced vascular dysfunction. We hypothesized that PARPi attenuates VEGFi-induced vascular injury through TRPM2/Ca
2+
-dependent pathways. Human vascular smooth muscle cells (hVSMC), human aortic endothelial cells (HAEC), and mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone (3μM) or in combination with olaparib (1μM). Wire myography was used to assess vascular function. Axitinib reduced ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), an effect blocked by olaparib. U46619- and ET-1-induced vasoconstriction were increased by axitinib (% KCl-
U4
: 101.2 [Ct] vs. 141.4 [Axi];
ET-1
: 122.6 [Ct] vs. 152.5 [Axi]), an effect not observed with axitinib plus olaparib. TRPM2 channel blocker (8-Br-cADPR; 1μM) attenuated the hypercontractile effects and endothelial dysfunction induced by axitinib. Axitinib increased ROS production in hVSMC (RUL: 0.8±0.2 [Ct] vs. 1.1±0.09 [Axi]) and HAEC (0.7±0.4 [Ct] vs. 1.2±0.1 [Axi]), stimulated phosphorylation of the inhibitory site of eNOS (a.u.: 0.99±0.35 [Ct] vs. 1.35±0.10 [Axi]) and induced exaggerated Ca
2+
influx (AUC: 17541±4708 [Ct] vs. 22249±1438 [Axi]) in hVSMC. These effects were blocked by olaparib and 8-Br-cADPR. Axitinib also induced phosphorylation of MLC20 in hVSMC (a.u.: 0.028±0.02 [Ct] vs. 0.04±0.01 [Axi]) and aorta (a.u.: 0.3±0.01 [Ct] vs. 0.5±0.001 [Axi]). Our data indicate that PARP/TRPM2 inhibition attenuates axitinib-mediated vascular dysfunction and normalizes impaired hVSMC and HAEC signalling induced by VEGFi. We define a putative vasoprotective effect of olaparib that may ameliorate vascular injury and hypertension induced by VEGFi in cancer treatment.
Abstract 45: Sex Differences Of Renal11β-hsd1 And 11β-hsd2 Expression In A Doca-salt Model Of Hypertension.
Authors: Belanger Kasey , Sullivan Jennifer C
Published: August 2021

The balance between hydroxysteroid dehydrogenase 1 (11β-HSD1) and hydroxysteroid dehydrogenase 2 (11β-HSD2) have been implicated in the regulation of mineralocorticoid effects. We have previously shown in the DOCA-salt model of hypertension that males have a more pro-inflammatory immune profile and higher BP than females. The current study tested the hypothesis that males have a higher ratio of 11β -HSD1 to 11β -HSD2 and that preventing DOCA-salt induced increases in BP significantly shifts that ratio.At 10 wks of age, male and female Sprague-Dawley rats were anesthetized and a right uni-nephrectomy (UNX) was performed. After one week of recovery, rats were randomized to the following groups: 1) UNX controls, 2) DOCA-salt (200 mg) with 0.9% saline to drink, or 3) DOCA-salt with saline + hydrochlorothiazide (HCTZ; 55 mg/kg/day) and reserpine (RES; 4.5 mg/kg/day. After 3 weeks of treatment, the remaining kidney was isolated to measure mRNA expression of 11β-HSD1 and 11β-HSD2 via RT-qPCR.Control UNX males had a higher 11β-HSD1:11β-HSD2 ratio than females (0.9 ± 0.15 vs 0.3 ± 0.04; P=0.02). After DOCA-salt, 11β-HSD1 increased in both males and females (2.5 ± 0.1 vs. 1.3 ± 0.08; P
treatment
<0.0001). Males maintained a higher 11β-HSD1:11β-HSD2 ratio as well has had a higher increase in 11β-HSD1 to 11β-HSD2 ratio than females (P
sex
=0.04; P
interaction
=0.04) after DOCA-salt. With HCTZ/RES treatment, 11β-HSD1 to 11β-HSD2 ratios significantly decreased in both males and females (1.9 ± 0.5 vs. 0.8 ± 0.09; P
treatment
=0.002), but males maintained a higher 11β-HSD1:11β-HSD2 ratio vs females (P
sex
=0.002; P
interaction
=0.54). Our data suggests that there are sex differences in the balance of renal mRNA expression of 11β-HSD1 and 11β-HSD2, with males having a greater 11β-HSD1:11β-HSD2 ratio compared to females. Preventing DOCA-salt induced increases in BP significantly shifts this ratio through an upregulation of 11β-HSD2 in both sexes.
Abstract 48: Military Sexual Trauma Is Associated With Incident Hypertension In A 16-year Cohort Study Of 1.2 Million Young And Middle-aged Men And Women
Authors: Gaffey Allison E , Rosman Lindsey , Haskell Sally G , Brandt Cynthia A , Sico Jason J , Bastian Lori A , Dziura Jim , Burg Matthew M
Published: August 2021

Introduction:
Exposure to traumatic events and the sequelae [e.g., posttraumatic stress disorder (PTSD) and poor health] are linked to incident cardiovascular disease (CVD) in military and community samples. Veterans, especially women, are 3-times as likely to experience sexual harassment and assault [military sexual trauma (MST)] compared to civilian populations. It is unknown if exposure to MST is independently associated with risk of incident hypertension.

Methods:
We conducted a retrospective analysis to assess the effect of MST on the risk of incident hypertension, defined as a medical record diagnosis, meeting clinical threshold based on blood pressure in vital sign records, or use of antihypertensive medication, in a cohort of 1,177,944 young and middle-aged veterans (mean age= 30.2 [SD:9.2], 12% women) using nationwide data from the Veterans Health Administration from 2001 to 2017. Time-varying multivariate Cox models were computed to estimate hypertension risk by MST status while sequentially adjusting for demographics, lifestyle factors, CVD comorbidities, and psychiatric disorders. Sensitivity analyses controlled for healthcare utilization based on the number of primary care visits over two years after military discharge.

Results:
During 16 years of follow-up (mean=9.6 years [SD:4.0]), 33,881 veterans screened positive for MST (65% women) and 307,332 patients were diagnosed with hypertension. The overall incidence rate of hypertension was 305.1 events per 1,000-person years. MST was associated with a 30% greater risk of hypertension in unadjusted models (hazard ratio [HR], 1.30 [95% CI, 1.28-1.33]) and remained significantly associated with hypertension in models that adjusted for demographics, lifestyle factors, CVD comorbidities, PTSD, anxiety, and depression (adjusted HR, 1.10 [95% CI, 1.08-1.12]. In sensitivity analyses, the effect of MST remained significant when controlling for healthcare utilization (HR, 1.11, [95% CI, 1.09-1.13]).

Conclusions:
In this large prospective cohort of young adults, MST was associated with an increased risk of hypertension after controlling for established risk factors. Further research is needed to determine if early identification of MST improves cardiovascular risk management.
Abstract 52: KDIGO (Kidney Disease: Improving Global Outcomes) Guideline Update On The Management Of Blood Pressure In Chronic Kidney Disease: What’s New And What’s Different From Other Guidelines
Authors: Cheung Alfred , Chang Tara I , Cushman William , Furth Susan , Hou Fan Fan , Ix Joachim H , Knoll Gregory , Muntner Paul , Pecoits-Filho Roberto , Sarnak Mark J , Tobe Sheldon W , Tomson Charles , Mann Johannes
Published: August 2021

Introduction:
In 2012, KDIGO released a guideline on BP management in CKD not receiving dialysis. The emergence of new trials and meta-analyses coupled with wider recognition of the importance of standardized BP measurement protocols have prompted a call to update the 2012 guideline. This summary will outline the changes to the prior recommendations and highlight similarities to guidelines from ACC/AHA and ESC/ESH.

Methods:
A systematic review was undertaken to formally assess the following issues: 1) BP measurement; 2) lifestyle interventions; BP management in 3) patients with CKD, with and without diabetes, 4) kidney transplant recipients, and 5) children with CKD.

Results:
A total of 6863 citations were screened. Of these, 290 RCTs, 14 observational studies, and 35 systematic reviews were included in the evidence review. A major addition to the KDIGO 2021 guideline is a chapter devoted to BP measurement. KDIGO recommends the use of standardized office BP over routine BP. Out-of-office measurements (ABPM, HBPM) can be used to complement standardized readings. This emphasis on standardized office BP measurement is similar to recommendations from ACC/AHA and ESC/ESH. A systolic BP target of <120 mm Hg is suggested; however, the guidance emphasizes that the target is only applicable when BP is measured using standardized office protocols. RASi are the preferred agents for adults with CKD with increased albuminuria. For lifestyle interventions, dietary sodium intake should be limited to <2 g/day, and ≥150 minutes/week of physical activity is recommended. A BP target of <130/80 mm Hg and use of CCB or ARB are preferred in kidney transplant recipients. BP in children with CKD should be guided by 24-hour MAP using ambulatory monitoring, targeting ≤50th percentile for age, sex, and height. Similar to ACC/AHA and ESC/ESH guidelines, KDIGO also encourages shared-decision making between patients and clinicians in the individualization of BP therapy.

Conclusions:
KDIGO has revised its guideline for BP management in CKD based on a rigorous development process and emerging new evidence underscoring the importance of standardized office BP measurement and a lower systolic BP target of <120 mm Hg for achieving potential cardiovascular, kidney, and mortality benefits.
Abstract 59: Vascular Glucagon-like Peptide 1 (GLP-1) Signaling Is Reduced In Obesity-related Hypertension In Female Rats
Authors: Kiernan Risa , Persand Dhandevi , Maddie Nicole , Carrillo-Sepulveda Maria Alicia
Published: August 2021

Obesity is a major risk factor for hypertension. Obesity-related hypertension impacts more women than men, but the underlying mechanisms remain unclear. GLP-1, an incretin released after food intake, exerts vasculo-protective effects. Human studies have shown that GLP-1 levels are decreased in obese patients. We hypothesized that vascular GLP-1 signaling is reduced in obesity and weight loss rescues this signaling. Eight-week-old female Wistar rats were randomized into three groups: LEAN (n=9) received a chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) for 28 weeks, OBESE (n=7) received a Western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein) for 28 weeks, and reverse obese (rOBESE) (n=7) received a Western diet for 18 weeks followed by 12 weeks of chow diet. The OBESE group exhibited increased body weight (395.6 vs. 285.4g LEAN, p<0.0001) and body mass index (6.8 vs. 5.1kg/m
2
LEAN, p<0.01), while the rOBESE group lost weight (337.0 vs. 395.6g OBESE, p<0.01). Direct measurement of blood pressure (BP) using a pressure-volume catheter inserted in the carotid artery revealed increased systolic (142.8 vs. 117.2mmHg LEAN, p<0.001), diastolic (125.0 vs. 92.7mmHg LEAN, p<0.001), and mean arterial BP (130.9 vs. 107.9mmHg LEAN, p<0.001) in the OBESE group. The rOBESE group sustained elevated systolic BP (139.1 vs.117.2mmHg LEAN, p<0.05). Endothelium-dependent vasodilation studies assessed by wire myograph demonstrated that the OBESE group exhibited impaired response to acetylcholine (Emax: 82.7% vs. 97.9% LEAN, p<0.001). Similar vascular impairment was observed in the rOBESE group (EMax: 81.3% vs 97.9% LEAN, p<0.001). Strikingly, while decreased GLP-1 serum levels in the OBESE group (10.6 vs. 18.4pM/mL LEAN, p<0.05) returned to normal levels in the rOBESE group (19.4 vs.18.4pM/mL LEAN), GLP-1 receptor protein expression was reduced in both groups (24% decrease in OBESE, 52% decrease in rOBESE) as compared to LEAN. Our results support that GLP-1 signaling is implicated in obesity-related vascular dysfunction in females and weight loss does not guarantee recovery of protective GLP-1 signaling nor improvement of vasodilation.

Conclusion:
GLP-1 is a potential therapeutic target for obesity-related hypertension in females.
Abstract MP02: Acute Increases Of Renal Perfusion Pressure Activate Mechanistic Target Of Rapamycin Complex 1 And Increase Macrophage Infiltration In The Kidney Of Sprague Dawley Rats.
Authors: Shimada Satoshi , Yang Chun , Kumar Vikash , Mattson David L , Cowley Allen W
Published: August 2021

Studies were carried out to determine whether acute elevation of renal perfusion pressure (RPP) activates the mechanistic target of rapamycin complex 1 (mTORC1) and inflammation-related genes which may trigger a rapid infiltration of immune cells. RPP was elevated by 40 mmHg (HP group) for 30 minutes in male SD rats (n=5, 10-12 weeks of age) while measuring renal blood flow (RBF; Transonic ultrasonic probe) and urine flow rate. Sham rats (Sham group) were studied in the same way, but RPP was not changed. Since initial studies found that the acute increase of RPP resulted in activation of mTORC1 (pS6
S235/6
/S6; P<0.05) but not mTORC2 (pAKT
T308
/AKT ), the effects of inhibition of mTORC1 with rapamycin (Rapa) pretreatment (1.5 mg/kg; n=10) were then determined (HP+Rapa group). RBF was well autoregulated in both HP and HP+Rapa treated rats averaging 6.9 ± 0.5 vs 7.0 ± 0.8 ml/min/gkw in HP (p=0.72) and 8.1 ± 0.8 vs 8.4 ± 0.5 in HP+Rapa group (p=0.34) with a 40 mmHg elevation of RPP. Pressure-natriuresis was unexpectedly blunted in HP+Rapa treated rats increasing from 0.40 ± 0.21 to 4.0 ± 1.1 in HP rats compared to 0.21 ± 0.07 to 2.3 ± 0.5 μmol/min/gkw; p<0.05) in the HP+Rapa treated rats. Urine volumes were similarly affected. Elevation of RPP increased the mTORC1 activity (pS6
S235/6
/S6) in renal cortex (2.8 ± 0.4 vs 4.8 ± 0.5 A.U.; p<0.05, n=5) and outer medulla (2.0 ± 0.3 vs 5.0 ± 0.6 A.U.; p<0.05, n=5) of HP rats compared to Sham. Rapa treatment suppressed this activation. rtPCR analysis found increased mRNA expression of lipocalin-2 (Lcn2; involved innate immune responses; p<0.05), heme oxygenase (Hmox1; p<0.05) and cyclooxygenase 2 (Cox2; p=0.08) in HP rats compared to Sham, responses which were generally blunted by Rapa. Importantly, as determined by immunohistochemistry, CD68 positive macrophage staining was significantly increased (p<0.001) with elevation of RPP in HP compared to sham rat kidneys. This was significantly reduced by Rapa treatment (p<0.001). We conclude that the mTORC1 pathway can be activated very quickly following elevations of RPP and appears to be responsible for rapid macrophage infiltration which is prevented by Rapa treatment. So too, inhibition of mTORC1 with Rapa reduced the pressure-diuresis response through yet unknown mechanisms.
Abstract MP08: New Function Of Sox6 In Renovascular Hypertension Induced Oxidative Stress And Kidney Damage Through Renin, Prorenin And The (pro)renin Receptor Expression Control.
Authors: Saleem Mohammad , Barturen-Larrea Pierina , Dikalov Sergey I , Gomez Jose A
Published: August 2021

Introduction:
During renovascular hypertension induced by renal artery stenosis (RAStenosis), smooth muscle cells are recruited to produce and release renin compensating for the decrease in renal perfusion. In renovascular hypertension, renin expression increases causing a surge in angiotensin II, oxidative stress and kidney damage. Here we present a new function of the transcription factor Sox6 in kidney injury and oxidative damage during RAStenosis.

Methods:
We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Ren1d
Cre
/Sox6
fl/fl
-Sox6-KO). We developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to induce RAStenosis. We measured superoxide production (pmol/mg pr) in kidney using high-performance liquid chromatography in Sox6-KO and Ren1d
Cre
/Sox6
wt/wt
(Sox6-WT) littermates. Renin, prorenin, (pro)renin receptor (PRR) and N-GAL expressions were measured using Western blot using β-actin as housekeeping gene. Western blot band density analysis was performed using ImageJ. Kidney injury was determined by measuring creatinine clearance.

Results:
We found that Sox6-KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, p<0.01), and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, p<0.05) and mice are protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, p<0.01), and kidney injury measuring N-GAL expression (1.3 vs. 2.7, SEM=0.38, n=6-8, p<0.01) and creatinine clearance (2372 vs. 1341, SEM=342.3, n=4-5, p<0.05). Furthermore, we found that the levels of superoxide were significantly lower in Sox6-KO mice compared to Sox6-WT littermates (218 vs 47, SEM=50.6, N=7, P<0.01). The expression of PRR was significantly lower in Sox6-KO compared to Sox6-WT during RAStenosis (1.23 vs. 0.72, SEM=0.33, n=2-5, p<0.01).

Conclusions:
Our results show that Sox6 depletion in renin expressing cells inhibits the increase in renovascular hypertension and prevents the increase in renin, prorenin, PRR, and N-GAL expression as well as superoxide production, preserving creatinine clearance during RAStenosis. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.