bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Natriuretic and Diuretic Response to Uroguanylin is Blunted in Dahl‐Salt Sensitive Rats
Authors: Nascimento Nilberto Robson Falcão , Martins Isabel Cristina Mendonça Torres , Lessa Lucília Maria Abreu , Santos Cláudia Ferreira , Fonteles Manassés Claudino 
Published: November 2023

Uroguanylin (UGN) is a 17 aminoacids long peptide with diuretic and natriuretic activity. UGN, an intestinal natriuretic peptide, is delivered to the kidney as an unprocessed propeptide, prouroguanylin (pro‐UGN). Circulating pro‐UGN is processed to its active natriuretic form exclusively within the renal tubules. The circulating levels of pro‐UGN and the urinary levels of UGN are increased during sodium overload and this natriuretic peptide and the kidney response to UGN is increased in rats maintained in a high salt intake. We hypothesized that the diuretic and natriuretic response to UGN are altered in Dahl‐salt sensitive rats (DS) as compared to Wistar (WR) rats. Dahl‐salt sensitive (DS) rats (n=5/group) received water with 1% NaCl during 15 days and the tail systolic blood pressure (mmHg) increased from 108.0±2.0 to 145.9±2.6 while no remarkable changes were observed in Wistar rats. After the end of this period, rats were anesthetized and prepared for classical renal clearance and hemodynamics studies. After a 1‐hour control period, UGN was intravenously infused at 100nmoles/kg/min rate during 1‐hour period and heart rate (HR), mean arterial pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), renal blood flow (RBF), urine output (V′), UNaV and fractional sodium excretion (FENa+) were evaluated during infusion and for an additional 1‐hour post‐infusion period. No significant changes were observed for HR, MAP, RVR or RBF in any group or period during the whole experimental period. UGN did not change GFR (ml/g/min) in WR rats but increased it from 1.7±0.8 to 4.4±1.1 in DS rats. In addition, UGN infusion induced a significant diuresis that was stable during the infusion and post‐infusion period. The urinary output (μL/g of kidney/min) increased from 6.7±1.1 to 21.6±5.4 (p<0.001) during the infusion with UGN in WR and from 5.7±2.6 to 11.5±3.6 in DS. Strikingly, the basal levels of UnaV (μEq/g of kidney/min) in DS are significantly lower than the levels observed for WR (0.04±0.01‐DS vs. 0.23±0.07‐p<0.001). The infusion of UGN increases UNaV from 0.23±0.07 to 0.48±0.01 (p<0.01) in WR and from 0.04±0.01 to 0.27±0.08 (P<0.001). Similarly, the basal FENa+ is remarkably lower in DS when compared to WR. DS rats excrete 10 times less sodium than WR. The infusion of UGN does not increase FENa+ (%) in DS but induced a 60% increase in in WR from 1.5±0.12 to 2.5±0.16 at the end of the infusion period. The diuretic and natriuretic effects of UGN are blunted in DS rats. The defect of this counter regulatory mechanism may have a role in the genesis and maintenance of hypertension in this strain of rats.Support or Funding InformationCNPq, FUNCAP and CAPES
Diuretic and Natriuretic Activity of a Lipid Induced by Fatty Acyl Amide Hydrolase Inhibition in Cultured Mouse Medullary Interstitial Cells
Authors: Daneva Zdravka , Dempsey Sara , Ahmad Ashfaq , Wolf Carl , Li Ningjun , Li Pin‐Lan , Ritter Joseph 
Published: November 2023

The endocannabinoid, anandamide (AEA, N‐arachidonoyl ethanolamine), is enriched in the renal medulla, a region implicated in the long‐term control of blood pressure. However, the role of AEA and its metabolizing enzymes, fatty acid amide hydrolase (FAAH) and cyclooxygenase‐2 (COX‐2), in the renal medulla are not well understood. In this study, cultures of mouse medullary interstitial cells (MMICs) from C57BL6 mice were established and characterized. Similar to inner medullary interstitial cells in mouse kidney sections in situ, cultured MMICs showed intense staining for tenascin C, a selective marker for medullary interstitial cells, and stained positively for immunoreactive COX‐2 and FAAH, and for the presence of lipid droplets by Oil Red O. Treatment of MMICs for 24 h with the FAAH inhibitor, PF3845, produced a marked increase in Oil Red O staining. Analysis of the chromatographic profiles of lipid extracts of the medium from vehicle‐ and PF3845‐treated MMIC cultures by reverse‐phase high pressure liquid chromatography (RP‐HPLC) with UV detection revealed a product that was responsive to treatment with PF3845. Levels of the product decreased when PF3845 was combined with the COX inhibitor, indomethacin. To assess the antihypertensive roles of the product, it was purified by RP‐HPLC of a larger scale extract and evaluated in anesthetized C57BL6 mice instrumented with a blood pressure probe in the carotid artery, a bladder cannula for collection of urine and an i.v. catheter implanted in the jugular vein for infusion of albumin‐saline. Continuous i.v. infusion of the lipid (0.1 AU/min for 20 min) had no effect on mean arterial blood pressure, but it increased urine volume and sodium and potassium excretion. The data suggest that the lipid is a diuretic‐natriuretic that is dependent on AEA or another ethanolamide and COX‐2 for its formation. Efforts are underway to identify the structure of the lipid.Support or Funding InformationSupported by NIH grant DK 102539
Aquaporin‐3 deficiency slows renal cystogenesis via regulation of AMPK/ERK/mTOR signaling
Authors: Yang Baoxue , Wang Weiling 
Published: November 2023

OBJECTIVEHuman autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous bilateral renal cysts that lead to a decline in kidney function over time. Previous studies reported aquaporin‐3 (AQP3) expression in cysts derived from collecting ducts in ADPKD. The aim of this study is to study the effect of AQP3 on ADPKD development.METHODSAQP3 deficient PKD mice and inducible PKD mice were established in this study. Effect of AQP3 on PKD development was studied with pathological and molecular biological techniques.RESULTSIn both models, kidney size and cyst number were ~30% smaller in AQP3 null PKD mice than in AQP3‐expressing PKD mice, with the difference due mainly to smaller collecting ducts cysts. In matrix cultured MDCK cyst model, AQP3 transfection promoted cyst enlargement. To investigate the mechanism of AQP3‐dependent cyst development, we detected related signaling pathways. It was found that the AMPK/ERK/mTOR signaling, as well as intracellular ATP, were down‐regulated after AQP3 deletion. In addition, overexpression of AQP3 increased intracellular ATP synthesis, and HIF1α and glucose transporter 1 expression.CONCLUSIONWe conclude that AQP3 depletion retards cyst growth, primarily due to AQP3‐dependent energy metabolism. These findings identified the AQP3 as a potential therapeutic target for treating ADPKD.Support or Funding InformationThis work was supported by National Natural Science Foundation of China grants 31200869, 81261160507, 81330074 and 81170632, and the 111 Project.
Exogenous administration of hydrogen sulphide enhances the responsiveness of α1D‐adrenoreceptors in the kidney of rats with left ventricular hypertrophy
Authors: Ahmad Ashfaq , Sattar Munavvar Zubaid Abdul , Azam Maleeha , Khan Safia Akhtar , Abdullah Nor Azizan , John Edward James 
Published: November 2023

Present study explored the interaction of hydrogen sulphide (H2S) and α1D‐adrenoreceptors of the kidney. This study investigated the functional contribution of α1D‐adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy treated with H2S.MethodologyThe LVH was induced by isoprenaline administration (5mg, S/C, every 72 hours for 2 weeks) and caffeine in drinking water (62mg/L) for 2 weeks while H2S was given 56μM/kg for 5 weeks as intra‐peritoneal injection. The responsiveness of α1D to exogenous noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) in the absence and presence of BMY 7378 was studied.ResultsThe plasma and kidney concentration of H2S in LVH group was significantly lower (P<0.05) than the control (LVH vs. control, 16±1 and 24±2 vs. 54±2 and 38±1 μM). The exogenous administration of NaHS in LVH resulted in a significant increased (P<0.05) in plasma and kidney concentration of H2S when compared to their untreated counterparts (LVH‐H2S vs. LVH, 54±2 and 67±2 vs. 16±1 and 24±2 μM). Induction of LVH significantly blunted (P<0.05) the responses of NA, PE and ME in saline phase of LVH by 21%, 23% and 28 % when compared to respective phase of Control group. Blocking of α1D‐adrenoceptor by low dose and high dose of BMY did not significantly reduced the responses to NA, PE and ME in low dose and high dose phases of LVH when compared to responses produced by NA, PE and ME in same phases of Control group. Exogenous administration of H2S significantly increased (P<0.05) the responses by α1D‐adrenoceptor to NA, PE and ME in LVH‐H2S in low and high dose phases by 52% and 30 %, 120% and 206 % while 116% and 423 % respectively when compared to responses produced by α1D‐adrenoceptor to NA, PE and ME in same phases of LVHConclusionTreatment with H2S augmented the responsiveness of α1D‐adrenoceptor subtypes in the kidney of rats with LVH.Support or Funding InformationThe Institute of Postgraduate Studies (IPS) is acknowledged for the provision of a USM fellowship (Teaching) to Ashfaq Ahmad (APEX (1002/JHEA/ATSG4001). The authors fully acknowledge USM‐RU grant no. 1001/PFARMASI/815078 for this work.
PDI via Keap1/Nrf2 pathway Regulates Redox Balance, Renal AT1 Receptor Function and Blood Pressure
Authors: Wang Xitao , Asghar Mohammad 
Published: November 2023

Oxidative stress is reported to play a vital role in the regulation of renal angiotensin AT1 receptor (AT1R) function and blood pressure (BP). This indicates that redox balance is crucial for normal AT1R function and BP. We tested a hypothesis that Protein Disulfide Isomerase (PDI), an enzyme that has diverse biological activity, via Keap1/Nrf2 pathway, regulates cellular redox homeostasis, AT1R function and blood pressure. To test the hypothesis, we treated adult Sprague Dawley (SD) rats with bacitracin, a PDI inhibitor for 14 days and determined various parameters. We found that bacitracin treated compared to vehicle treated rats, showed higher blood pressure. This was associated with greater diuresis and natriursis in response to AT1R blocker candesartan in bacitracin treated rats, indicating higher AT1R function in these rats. Moreover, bacitracin treated rats had higher oxidative stress and renal injury, as determined by measuring oxidative stress markers: urinary 8‐isoprostane, renal protein carbonyls and renal nitrotyrosine levels as well as urinary kidney injury molecule‐1 levels, respectively. This was associated with reduced antioxidant capacity and impaired Nrf2 transcription factor activity, involved in maintaining antioxidant capacity. Further, Kelch like ECH associated protein 1 (keap1) levels, an endogenous repressor of Nrf2, and tyrosine 216 phosphorylated GSK3β protein, which causes Nrf2 nuclear export were higher in bacitracin treated rats. Moreover, Nuclear Nrf2 levels in human kidney 2 cells treated with bacitracin also decreased compared to control cells. These data suggest that PDI via keap1/Nrf2 pathway regulates redox balance, AT1R function and BP in SD rats.Support or Funding InformationNIH/NIA, AG039856
Characterization of potassium channels involved in the mechanisms of vascular relaxation induced by omega‐3 polyunsaturated fatty acids in rat arteries; a critical role for KATP channels
Authors: Limbu Roshan , Cottrell Graeme S , McNeish Alister J 
Published: November 2023

IntroductionFish oils are involved in the vasodilation of arteries and studies indicate that the main components involved are omega‐3 polyunsaturated fatty acids (n‐3 PUFA) that include docosahexaenoic acid (DHA) and eicosapentaenoic acids (EPA) (1). We previously demonstrated that inhibition of KCa channels partially attenuates fish oil mediated relaxation in rat mesenteric arteries (2). Since a considerable proportion of the relaxation to n‐3 PUFA was residual to blockade of KCa, vasodilation pathways involving other types of potassium channels could be involved. Studies report that the predominant vasodilation mechanisms can differ depending upon the type of artery an (3). Therefore, our main objective was to investigate these pathways in n‐3 PUFA‐induced relaxation of both large muscular (aorta) and resistance rat arteries (mesenteric).Methods2mm segments of rat arteries were mounted on a wire myograph and cumulative concentration response curves to DHA or EPA (10nM–30μM) mediated relaxation were examined following pre‐constriction with U46619 (10–500nM) in rat aorta and mesenteric artery. In certain experiments isotonic Krebs solution containing high [KCl] (final bath concentration 30mM; inhibits hyperpolarization mediated by potassium channels) or PNU37883A (3μM), a KATP blocker were administered prior to assessing relaxation. Relaxation was expressed as mean % relaxation of U46619‐induced constriction ± SEM of n animals. Data was analysed using one‐way ANOVA with Bonferroni's post‐test. P‐value of ≤ 0.05 was considered as being statistically significant.ResultsNon‐selective inhibition of potassium channels with high [KCl] Krebs virtually abolished both DHA‐ and EPA‐induced relaxation in rat aorta. Furthermore, High [KCl] Krebs also partially inhibited relaxation mediated by both DHA and EPA in rat mesenteric artery. Inhibition of KATP with PNU37883A attenuated fish oil‐induced relaxation in rat aorta. Consistently, in rat mesenteric artery PNU37883A also inhibited both DHA‐ and EPA‐induced relaxation.ConclusionsWe demonstrate that the non‐selective blockade of potassium channels abolished both DHA‐ and EPA‐mediated relaxation of rat aorta. Furthermore, inhibition of potassium channels in the resistance mesenteric artery also inhibited relaxation induced by DHA and EPA. We further characterised the potassium channels involved; blockade of KATP channels inhibited both DHA and EPA induced relaxation in rat aorta and mesenteric artery. This is the first study indicating that DHA and EPA evoke relaxation through KATP in both rat large muscular and resistance arteries. We will incorporate patch clamp in our future studies to investigate whether n‐3 PUFA directly regulate KATP channels.Support or Funding InformationThis work was supported by British Heart Foundation (PhD Studentship no. FS/14/33/30799)
Nstpbp5185 attenuates the progression of neointima formation in a rat model of balloon injury
Authors: Huang Tur‐Fu , Huang Shiu‐Wen 
Published: November 2023

BackgroundAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play an important role in the development of restenosis. Platelet‐derived growth factor (PDGF) is one of the major factors in triggering restenosis. Nstpbp5185 is a potent TP receptor antagonist, exhibits anti‐thrombotic activities.Material and methodsIn an effort to figure out the anti‐restenosis effect of nstpbp5185, we investigated its effects on VSMC proliferation, migration in vitro and neointima formation in rat balloon injury model in vivo.ResultsOur findings demonstrated that nstpbp5185 inhibited PDGF and U46619‐induced VSMC proliferation and PDGF‐induced migration in a concentration‐dependent manner. Furthermore, nstpbp5185 also concentration‐dependently repressed PDGF‐PDGFR signaling pathway in VSMCs. In addition, in vivo experiments showed that intraperitoneal administration of nstpbp5185 at 1 mg/kg/day significantly attenuated neointima formation in balloon‐injured rat carotid arteries.ConclusionsOur results reveal that nstpbp5185 inhibits PDGF‐induced VSMC proliferation and migration, resulting in attenuation of neointima formation. Its therapeutic potential for treating restenosis after percutaneous transluminal coronary angioplasty (PTCA) warrants further evaluation.
Bazedoxifene Induces Greater Vascular Responses than Estradiol Independent of Sex and GPER
Authors: Zimmerman Margaret A. , Lindsey Sarah H. 
Published: November 2023

Conjugated estrogens (CE) combined with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA) is a novel menopausal hormone therapy that provides a progestin‐free option for women with an intact uterus. While the impact of estrogen (E2) on the vascular system has been extensively studied, less is known about the response to BZA. Previous work from our laboratory shows that many of the beneficial actions of estrogen in the vasculature are mediated by the G protein‐coupled estrogen receptor (GPER). Since previous generation SERMs bind to GPER in various tissues, we hypothesized that BZA may induce greater vascular effects than estradiol due to increased GPER activation. Mesenteric resistance arteries were isolated from male and female wildtype (WT) and GPER knockout (KO) mice between 18–24 weeks old. Vessel reactivity was measured via wire myography in response to increasing doses of phenylephrine (PE), sodium nitroprusside (SNP), bazedoxifene acetate (BZA), and 17β‐estradiol (E2). In males, BZA‐induced relaxation was significantly greater than E2 in both WT (BZA: 84 ± 7% vs. E2: 50 ± 5%; P<0.001) and KO vessels (BZA: 72 ± 11% vs. E2: 55 ± 4%; P<0.001). Similarly, BZA was a better vasodilator than E2 in females (BZA: 94 ± 1% vs. E2: 57 ± 6%; P<0.001), and was not altered by GPER deletion (BZA: 93 ± 1% and E2: 60 ± 6%; ns). To further assess the impact of BZA on vessel reactivity, mesenteric arteries were pre‐treated with either 10−9 M BZA, E2, or vehicle (0.1% DMSO) before being exposed to increasing doses of PE. In male WT and KO vessels, BZA blunted the response to PE‐induced contraction (WT Veh: 178 ± 11% vs. BZA: 145 ± 32%; P<0.001; KO Veh: 154 ± 5% vs. BZA: 120 ± 19%; P<0.001). This effect was exclusive to BZA and was not observed in male WT and KO vessels pre‐treated with E2 or DMSO (WT E2: 173 ± 20% and KO E2:160 ± 6%; ns). In female WT and KO arteries, pre‐treatment with BZA also opposed PE‐induced contraction (WT Veh: 159 ± 15% vs. BZA: 61 ± 10%; P<0.001; KO Veh: 173 ± 7% vs. BZA: 109 ± 20%; P<0.001), while E2 again failed to attenuate PE contraction (WT E2: 175 ± 20% and KO E2:189 ± 9%; ns). To assess whether BZA enhances nitric oxide‐induced relaxation, vessels were pre‐treated with BZA, E2, or DMSO prior to the SNP relaxation curve. Neither E2 nor BZA altered the response to SNP in male or female, WT or KO vessels. The current study demonstrates that BZA opposes vasoconstriction of mesenteric arteries to a greater degree than non‐selective E2, and this effect is independent of sex and GPER. Therefore, BZA may provide additional vascular benefits in menopausal hormone therapy and in turn promote a more positive cardiovascular profile in postmenopausal women.Support or Funding InformationNational Institutes of Health Grant 4R00HL103974 to S.H.L and American Heart Association Postdoctoral Fellowship Award #16POST27600001 to M.A.Z.
Resveratrol's initial transient enhancement of adrenergic contractions of rat tail arterial tissues involves a mechanism limiting its ability to exert a later sustained relaxation
Authors: Stom Sayra M , Peuler Jacob D 
Published: November 2023

We have reported that resveratrol can enhance as well as relax adrenergic contractions of arterial tissue rings prepared from both proximal (conductance) and distal (resistance) segments of the long ventral tail artery of the rat (Stom, JSMR 2016; 52:18–35). While the enhancing action only occurred in approximately half of our ring preparations (from proximal and distal segments alike), it always appeared immediately after administration before the later, more sustained relaxing effect (which occurred in all preparations) became apparent. Thus, the enhancing effect seemed to be only transient in duration. However, that does not rule out the possibility of its mechanism lasting long enough to limit the degree to which resveratrol eventually causes relaxation. To determine if that were true, we re‐examined data from our original arterial ring preparations to see if the half in which early transient enhancement occurred showed less eventual relaxation compared to the half in which they did not occur. Indeed, that was the case. This provides a novel explanation for why long‐term administration of resveratrol in vivo is reported to lower arterial blood pressures in some clinical studies but not in others, as highlighted in recent reviews (e.g. Liu, Clin Nutr 2015; 34: 27–34).Support or Funding InformationMWU Biomedical Masters Program
Understanding the nature of toxicity of Parkinson's disease associated alpha‐synuclein familial mutants H50Q, G51D, and A53E with yeast models
Authors: Ong Emily Nicole , Tembo Maiwase , Mwale Chisomo , Marshall Morgan , Alvarado Charles , Buabeng Michael , Kukulka Natalie , DebBurman Shubhik 
Published: November 2023

Parkinson's disease (PD) is associated with the aggregation and misfolding of alpha‐synuclein in midbrain dopaminergic neurons. The gene for alpha‐synuclein has six known mutations that directly cause familial forms of PD. The pathological determinants of three of these mutants (A30P, E46K, and A53T) are well characterized in diverse model systems and they that reveal that each mutant affects cellular toxicity in distinctive ways. The three more recently discovered familial mutants (H50Q, G51D, and A53E) are not extensively studied. We expressed H50Q, G51D, and A53E mutants in budding and fission yeasts model systems and hypothesized that each would generate toxicity by altering their membrane association and aggregation properties, and by disrupting cellular pathways including nitrative stress responses and endocytosis, but each would do so in distinctive ways. First, we found that the H50Q and A53E mutants were toxic to yeast, and bound membranes and aggregated within yeast, while G51D was cytoplasmically diffuse and nontoxic. Secondly, and surprisingly, we found that G51D mutant dominated over H50Q and A53E when these mutants were combined in double/triple mutants. Thirdly, we asked whether the loss of the original amino acid or the gain of the new amino acid in each new familial mutant is responsible for disease. We created four substitution mutations for H50Q, G51D, and A53E in both yeasts models corresponding to the four functional classes of amino acids. We found that H50D was cytoplasmically diffuse and nontoxic, G51A bound membranes and aggregated like WT, G51E was cytoplasmically diffuse and nontoxic like G51D, and A53R was cytoplasmically diffuse and nontoxic, suggesting both the loss of the original amino acid and the gain of the new amino acid are key. Finally, we are currently characterizing these familial mutants in yeast strains altered for endocytosis, nitrative stress, and sumoylation. Collectively, this work adds insight into the pathogenicity of different familial PD mutants of alpha‐synuclein.Support or Funding InformationE.O. was funded by Parkinson's Disease Foundation