bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of sex‐specific regulation of vascular soluble epoxide hydrolase in flow‐induced vasodilator responses
Authors: qin jun , Kandhi Sharath , Froogh Ghezal , Jiang Houli , Sun Dong , Huang An 
Published: November 2023

We hypothesized that potentiating the bioavailability of endothelial epoxyeicosatrienoic acids (EETs) via deletion of the gene for soluble epoxide hydrolase (sEH), or downregulation of sEH expression, enhances flow/shear stress‐induced dilator responses (FID) of arterioles. Using male (M) and female (F) wild type (WT) and sEH‐knockout (KO) mice, isolated gracilis muscle arterioles (90–150 μm in diameter) were cannulated and pressurized at 80 mmHg. Basal tone and increases in diameter of arterioles as a function of perfusate flow (5, 10, 15, 20 and 25 μl/min) were recorded. The magnitude of FID was significantly smaller (14.9 ± 0.8 %PD at maximal flow rate), and associated with a greater arteriolar tone (61.5 ± 1.1 %PD at 80 mmHg) in M‐WT than F‐WT mice (maximal flow rate: 22.3 ± 2.1 and basal tone: 74.4 1.6 %PD), revealing a sex‐difference in FID. This sex‐difference was abolished by deletion of the sEH gene, as evidenced by an enhanced FID in M‐KO mice to a level comparable to those observed in F‐KO and F‐WT mice. These three groups of mice coincidentally exhibited an increased endothelial sensitivity to shear stress expressed as smaller WSS50 (8.9±1.3 in M‐KO; 7.9±1.0 in F‐KO and 8.7±1.1 in F‐WT) compared to M‐WT (12.4 2.0) and were hypotensive. Endothelial EETs that did not contribute to FID in M‐WT mice, participated in the mediation of enhanced FID in M‐KO, F‐KO and F‐WT mice, as evidenced by inhibiting the enhancement with PPOH (an EET synthase inhibitor). Protein expression of sEH was downregulated by approximately 4‐fold in vessels of F‐WT compared to M‐WT mice, paralleled with greater vascular EET levels that were comparable to those observed in both male and female sEH‐KO mice. In conclusion, sex‐different expression of sHE accounts for sex differences in FID of microvessels in gonadally intact mice, characterized as a female‐specific downregulation of sEH that imitates the action of deleting sEH gene, leading to the enhancement of FID in F‐WT mice identical to those in sEH‐KO mice.Support or Funding InformationThis work was supported by NIH grant HL070653
Hypertension and Type II diabetes are not associated with visceral inflammation or vascular remodeling/fibrosis in obese women
Authors: Fernandes Roxanne , Fink Gregory D , Galligan James J , Watts Stephanie W , Pereira‐Hicks Cristiane , Watson Ralph E , Lane Mindy , Xu Hui 
Published: November 2023

Hypertension (HT) and Type 2 diabetes (T2D) are more common in overweight and obese subjects, but mechanistic links have not been fully established. Some evidence indicates that low level inflammation, especially in visceral fat depots, provides one such link in part by promoting vascular remodeling/fibrosis. Here we sought to determine if inflammation and splanchnic vascular remodeling/fibrosis were more prevalent in obese women with hypertension and/or T2D than obese only.METHODSWe blindly evaluated H&E stained mesenteric vessels and perivascular adipose tissue obtained from 29 female patients who underwent Roux‐en‐Y bariatric surgery. Based on this evaluation, the patients were separated into two groups, according to the observed relatively prevalence and severity of histological alterations (vascular remodeling/fibrosis, angiogenesis, and inflammation). Tissues from 11 patients showed relatively mild histological changes (Group A), while tissues from the other 18 patients displayed more severe histological alterations (Group B). Based on their medical histories, the number of patients with HT, T2D, HT+T2D or neither condition (obese only: OO) were determined for both groups.RESULTSHT+T2D was slightly (but not significantly) higher in group B than group A (3/11, 27.7% vs 8/18, 44.4%). OO (3/11, 27.3% vs 5/18, 27.7%), HT (3/11, 27.3% vs 3/18, 16.6%), and T2D (3/11, 27.3% vs 2/18, 11.2%) were all similar in groups A and B. There were no differences in age (45 ± 3y vs 49 ± 2y), BMI (43.3 ± 3% vs 44.1 ± 2%) or occurrence of hyperlipidemia (6/11, 54.5% vs 9/18, 50%) between the two groups. To confirm our observations in H&E stained tissues, we randomly selected three patients from each category (OO, HT, T2D and HT+T2D), and evaluated vascular remodeling/fibrosis in Masson's trichrome stained tissues (for collagen) and macrophage infiltration into perivascular adipose tissue (CD 68 staining). The results showed no correlation between vascular remodeling/fibrosis, or adipose tissue inflammation, and HT or T2D.CONCLUSIONSOur studies do not support the hypothesis that inflammation and vascular remodeling/fibrosis in the splanchnic region cause hypertension or T2D in obese women.Support or Funding InformationSupported by NIH 2P01HL070687 (For Drs Fink, Galligan, Watts and Xu)
Sex‐specific transcriptomic regulation in the diseased human heart
Authors: Kararigas Georgios , Summer Holger , Baczko Istvan , Golz Stefan , Regitz‐Zagrosek Vera 
Published: November 2023

Pressure overload‐induced left ventricular (LV) hypertrophy and heart failure manifest differently between men and women. Transcriptional regulation is crucial in many (patho)physiological processes. We aimed at studying the impact of sex on global gene expression in LVs of men and women with aortic stenosis (AS) and end‐stage dilated cardiomyopathy (DCM) compared with LVs of men and women with no cardiovascular disorder (n = 5–10/group). Genome‐wide expression profiling was performed using the Affymetrix platform and the data were analyzed with R and Bioconductor considering adjusted P < 0.05 significant. In AS, fibrosis‐related genes were induced in male samples, while ribosomal and energy‐related genes were repressed. Female‐specific repressed genes in AS included extracellular matrix‐related and inflammatory genes, while members of the mitochondrial carrier protein family were induced. Similarly, pathway analysis revealed that fibrosis‐related pathways were induced in male AS samples, while inflammatory pathways were repressed in female AS samples. In DCM, male‐specific induced genes included several members of the immunoglobulin family, while a number of ribosomal and energy‐related genes were repressed. Female‐specific induced genes in DCM included those encoding several zinc finger proteins, while members of protein polyubiquitination were repressed. Pathway analysis revealed induction of ECM‐receptor interaction and inflammatory pathways in male DCM hearts, while the oxidative phosphorylation and proteasome pathways were repressed. In female DCM hearts, the Wnt and Hedgehog signaling pathways were induced, while the mTOR signaling pathway was repressed. The present findings offer an important insight into disease biology, a novel sex‐specific aspect of gene regulation in the human hypertrophied and failing heart, and may have a wide implication in the development of new and personalized therapies.Support or Funding InformationDZHK (German Centre for Cardiovascular Research)
Multiparametric Determination of Renal Hemodynamics and Oxygenation using Non‐Invasive Magnetic Resonance Imaging in Healthy Volunteers
Authors: Eckerbom Per , Cox Eleanor , Subasic Irfan , Weis Jan , Palm Fredrik , Hansell Peter , Francis Susan , Liss Per 
Published: November 2023

PurposeDue to the risks associated with using contrast media in patients with impaired renal function there is clearly a need for non‐invasive techniques measuring renal blood flow (RBF) and oxygenation. Current techniques include arterial spin labelling (ASL), blood oxygen level‐dependent (BOLD) magnetic resonance imaging (MRI) and phase contrast (PC). In addition to needing thorough validation, it is also important to know if RBF and oxygenation are influenced by circadian rhythm. Therefore, we determined total and regional RBF and regional oxygenation in healthy volunteers as a function of time of day using these MRI.Methods and MaterialsTotal RBF was determined by PC in renal arteries, regional RBF by ASL and regional oxygenation by BOLD in 6 healthy volunteers every fourth hour for a total of 24 hours resulting in 6 repeated measurements in each individual.ResultsAverage total RBF was 898±10 ml/min and 893±27 ml/min for right and left kidney, respectively, with a drop during evening‐night but with significant individual variations. Average cortical RBF was 289±7 and 274±8 ml/min/100g for right and left kidney, respectively, with highest values during the day and lowest values during the evening‐night. Cortical oxygenation was 52±1 and 49±1 ms for right and left kidney, respectively, with minimal circadian variation.ConclusionNon‐invasive MRI is able to quantify also substile changes in RBF. Furthermore, these results demonstrate that RBF is influenced by circadian variations which should be considered when designing future studies in order to elucidate the role of deranged RBF regulation for the development of kidney disease.
Renal hemodynamics and tubular function are preserved when hydroxyethyl starch is dosed to acutely restore blood pressure after blood loss in rats
Authors: Fu Yiling , Qiu Hongyu , Kelada John , Khang Ser , Honndorf Stefanie , Vallon Volker 
Published: November 2023

Hydroxyethyl starch (HES) is used clinically to replace blood loss and stabilize hemodynamics. However, the fate of HES in the kidney and the functional consequences on kidney function have not been fully investigated. The goal of this study was to determine whether a single application of hydroxyethyl starch, dosed to rapidly restore blood pressure (BP) following a blood loss, affects renal hemodynamics or transport when assessed one week later.MethodsUnder short‐term anesthesia, Sprague‐Dawley rats were subjected to a 25% blood loss over 6.25 min via the femoral vein. Immediately thereafter, Volulyte® 6% containing HES 130/0.4 (VOL) or Hextend® 6% containing HES 670/0.7 (HEX) or a balanced crystalloid solution (Isolyte®, ISO) were infused i.v. to restore BP within 4–4.5 minutes. Pilot studies established that this required doubling of the infused volume of ISO (20ml/kg) vs VOL and HEX (each 10ml/kg). Sham operated rats without blood loss/volume substitution were used as control (CON). One week later, renal function was determined in renal clearance studies (using 3H‐inulin and paramino hippurate [PAH]) under terminal anesthesia. N=10/group.ResultsBody weight, heart rate, and plasma concentrations of glucose, chloride, calcium, phosphate and hematocrit were similar among the 4 group (not shown). Mean arterial pressure (MAP), renal hemodynamics (including GFR and renal blood flow [RBF]), tubular reabsorption of fluid, chloride (Cl), glucose, calcium (Ca), and phosphate (P), and tubular secretion of PAH were likewise not different among the 4 groups (see table: MAP [mmHg]; GFR, RBF [ml/min]; FR‐Ex, fractional renal excretion [%]).

MAP
GFR
RBF
FR‐Ex
FR‐Ex
FR‐Ex
FR‐Ex
FR‐Ex
FR‐Ex

fluid
Cl
glucose
Ca
P
PAH

CON
121±5
2.5±0.1
19.3±2.0
1.0±0.1
0.3±0.1
0.1±0.1
0.9±0.2
2.3±1.1
391±39

ISO
121±5
2.4±0.1
18.4±2.0
0.9±0.1
0.4±0.1
0.1±0.1
0.9±0.1
3.8±1.5
392±43

VOL
118±3
2.5±0.2
19.2±3.1
0.9±0.1
0.3±0.1
0.1±0.1
0.9±0.1
2.5±1.0
410±72

HEX
126±3
2.3±0.2
19.3±3.5
1.1±0.2
0.5±0.2
0.1±0.1
1.0±0.2
3.3±1.4
422±54

ConclusionA single bolus infusion of VOL or HEX, dosed to acutely restore BP after a 25% blood loss in rats, does not alter renal hemodynamics or tubular transport function compared with sham operation or volume substitution with ISO, when assessed one week later.Support or Funding InformationNational Institutes of Health O'Brien Center (P30DK079337), Fresenius Kabi Deutschland GmbH
Impaired Renal Autoregulation after Ischemia‐Reperfusion Results from Loss of Dynamic Stability Normally Conferred by Tubuloglomerular Feedback
Authors: Thomson Scott C , Pham Hai , Bourgette Ryan , Singh Prabhleen 
Published: November 2023

BackgroundAutoregulation of renal blood flow (Q) results from combined actions of myogenic (Myo) and tubuloglomerular feedback (TGF) systems. Surprisingly little is known about intra‐renal hemodynamics or autoregulation after acute kidney injury.MethodWe subjected rats (n=13) to renal ischemia‐reperfusion (IR, bilateral pedicle clamp × 1h) or sham ischemia. After 4 or 24 hrs, rats were re‐anesthetized (inactin) and 2‐hr recordings made of spontaneous left renal blood flow (Q) and arterial pressure (BP) while measuring 2‐kidney inulin clearance (GFR). We examined the dynamic relationship between Q and BP by two methods: First, we generated admittance spectra from short‐term Fourier transforms. This is a proven method for detecting TGF and Myo systems, which give respective resonance peaks at 0.03 and 0.15 Hz. Second, we generated autoregulatory step responses by applying the projection theorem to approximate Q as a linear sum of past BP and expressed the result as the fractional compensation following an idealized unit step in BP. The step response out‐performs spectral methods for quantifying the efficiency of autoregulation.ResultsData from 4 and 24h were similar and are pooled. GFR was depressed after IR (0.5± 0.3 vs 2.1±0.3 ml/min, P<0.002) but Q was not (14.8±1.9 vs 13.6±2.0 ml/min, P=0.7). Spectral analysis detected Myo activity in both Sham and IR but detected TGF activity only in Sham. Step responses diverged during the 10–20s window where TGF normally contributes most. For BP disturbances lasting longer than 15s, fractional compensation was less by ~50% in IR vs Sham.InterpretationQ is rapidly restored after IR, while GFR remains low enough that BP fluctuations cannot produce a TGF signal, which derives from flow in the tubule. Without a contribution from TGF, overall autoregulatory efficiency is diminished and Q is susceptible to changes in BP. This has implications for how to manage patients recovering from acute kidney injury.Support or Funding InformationVeterans Administration Research Service and UCSD‐UAB O'Brien Center for Acute Kidney Injury (P30‐DK‐79337).
Increased Urinary Exosomal Kidney Injury Molecule‐1 in Patients with Type 2 Diabetes
Authors: George Jasmine , Meng Yuan‐Xiang , Huang Ming‐Bo , Morgan‐Billingslea Jan , Garba Halima , Bond Vincent , Zhao Xueying 
Published: November 2023

Diabetic nephropathy (DN), a leading cause of end‐stage renal disease, occurs in 25%–40% of patients with diabetes, highlighting the importance of early identification and management of DN. Urinary exosomes are 40–100 nm vesicles released by epithelial cells along the nephron and they may serve as biomarkers of renal dysfunction and structural injury. Kidney injury molecule‐1 (KIM‐1) is expressed on the apical membrane of dedifferentiated proximal tubule cells and its ectodomain can be cleaved and released into the urine in both rodents and humans with proteinuric kidney diseases. In this study, we investigated urinary exosomal KIM‐1 in type 2 diabetic patients to confirm its role as a non‐invasive biomarker for predicting kidney injury and dysfunction. Exosomes were prepared from spot urine samples of healthy (n=11), prediabetic (n=12) and type 2 diabetic patients (n=10) using serial ultracentrifugation. Nanoparticle tracking analysis (NTA) was applied to quantify the size and concentration of urinary exosomes. The majority of the captured particles had a size ranging from 20 nm to 100 nm with a peak size of 78±14 nm in healthy subjects, 67±10 nm in prediabetic, and 49±7 nm in diabetic patients with or without albuminuria. Urinary exosomes were significantly increased in diabetic patients (16.2±2.7 ×1010 particles/mg creatinine) compared to healthy donors (7.4±0.9 ×1010 particles/mg creatinine) or prediabetic patients (8.8±1.5 ×1010 particles/mg creatinine). As expected, soluble KIM‐1 was significantly increased in the urine of diabetic patients with microalbuminuria. Interestingly, Western blot also detected an increase in urinary exosomal KIM‐1 in the diabetic patients without microalbuminuria. In conclusion, type 2 diabetes is associated with an increase in urinary exosomes and exosomal KIM‐1 may represent a novel candidate biomarker in diabetic renal complication.Support or Funding InformationThis work was supported by the NIH SDK096441, 8G12MD007602 and 8U54MD007588.
Increased I‐mfa in Mesangial Cells Contributes to Increased Abundance of Fibronectin Protein in Diabetic Kidney
Authors: Chaudhari Sarika , Li Weizu , Wang Yanxia , Ma Rong 
Published: November 2023

Accumulation of extracellular matrix (ECM) proteins in glomerulus is one of early features of diabetic nephropathy. Glomerular mesangial cell (MC) is the major source of ECM. Inhibitor of Myogenic Family isoform a (I‐mfa) is a cytosolic protein interacting with components of the Wnt/β‐catenin pathway and of store‐operated Ca2+ signaling pathway, both of which are involved in the development of diabetic nephropathy. The present study was carried out to determine if I‐mfa in MCs promoted expression of fibronectin protein, a major component of ECM using in vitro and in vivo settings. In cultured human MCs, high glucose treatment (25 mM) significantly increased I‐mfa protein expression in time and dose dependent manners. Importantly, abundance of I‐mfa protein markedly increased in the renal cortex and glomerulus in streptozotocin‐induced diabetic mice. Furthermore, overexpression of I‐mfa increased fibronectin expression at protein level and knockdown of I‐mfa decreased fibronectin expression at mRNA level in human MCs. We then generated diabetes in I‐mfa−/− and wild type control mice by multiple injections of low dose streptozotocin. As expected, diabetes greatly increased fibronectin protein expression in renal cortex in wild type mice. However, this fibronectin response was significantly reduced in I‐mfa deficient diabetic mice. Consistently, histological examination showed a decrease in mesangial expansion in I‐mfa deficient diabetic mice compared to wilt type control mice. Taken together, our data indicate that diabetes increased I‐mfa expression in MCs, which stimulates fibronectin protein expression in glomerulus. Therefore, I‐mfa may be a potential therapeutic target for diabetic nephropathy.Support or Funding InformationUNTHSC Institutional Seed Grant, UNTHSC Doctoral student Bridge Grant, Sigma Xi Grant‐in ‐Aids Research Grant.
Renal effects of glucagon‐like peptide‐1 receptor knockout in Akita‐diabetic mice
Authors: Song Panai , Fu Yiling , Qiu Hongyu , Onishi Akira , Drucker Daniel J , Vallon Volker 
Published: November 2023

BackgroundGlucagon‐like peptide‐1 (GLP‐1) is a gut‐derived hormone that enhances glucose‐dependent insulin release and has anti‐oxidative and protective effects mediated through GLP‐1 receptor (GLP1R) in various tissues. Here, we determined whether the GLP1R has a pathophysiologic role in the diabetic kidney.MethodsGLP1R‐KO mice (C57BL/6J) were backcrossed to DBA2 background for at least 4 generations and crossed with heterozygous Ins2Akita mice, a genetic model of type 1 diabetes, to generate 4 experimental groups; i) WT (n=7), ii) GLP1R‐KO (n=14), iii) diabetic WT (n=6), and iv) diabetic GLP1R‐KO (n=10). Body weight, blood glucose, urine glucose and albumin to creatinine ratios, GFR (by plasma elimination kinetics of FITC‐sinistrin in conscious mice), and kidney weight were determined at 16 weeks of age.ResultsIn non‐diabetic mice, no significant differences were observed between GLP1R‐KO and WT for bodyweight (26.1±1.0 vs 26±1.3 g), blood glucose (127±4 vs 112±5 mg/dl), urine glucose (2.5±0.3 vs 3.6±0.8 umol/mg), albuminuria (39±7 vs 37±19 μg/mg), and GFR (18±1 vs 22±2 μl/min/g), while kidney weight tended to be reduced in GLP1R‐KO (7.8±0.2 vs 8.5±0.3 mg/g; P=0.064). In GLP1R‐KO and WT mice, diabetes increased to similar levels: blood glucose (515±21 vs 501±32 mg/dl), urine glucose (3504±426 vs 5515±864 umol/mg), albuminuria (117±41 vs 102±22 ug/mg), food and fluid intake (not shown), and GFR (28±2 vs 33±3 ul/min/g), associated with a similar reduction in body weight (23.1±0.9 vs 23.7±0.6 g). While diabetes increased kidney weight in GLP1R‐KO and WT to similar absolute levels (11.8±0.8 vs 10.3±0.4 mg/g), the diabetes‐induced fractional increase was enhanced in GLP1R‐KO vs WT (increase of 51 vs 21%).Conclusion1) On a predominant DBA2 genetic background, type 1 Akita diabetes increased blood glucose levels, GFR, kidney to body weight ratios, and albuminuria. 2) The effects of diabetes on blood glucose, GFR and albuminuria occurred independent of the GLP1R, whereas the absence of the GLP1R appeared to facilitate the diabetes‐induced increase in kidney to body weight ratios.Support or Funding InformationNational Institutes of Health (R01DK56248, P30DK079337) and AstraZeneca
The Impact of Elevations of Renal Perfusion Pressure and Hyperglycemia on MMP‐2 Expression
Authors: McPherson Kasi Christine , Womack Judson , Taylor Lateia , Fizer Brianca , Green DesTenee , Spires Denisha , Robinson Joihn , Williams Jan M 
Published: November 2023

The early stages of diabetic nephropathy (DN) are characterized by elevations in glomerular filtration rate (GFR) or renal perfusion pressure (RPP) that initiates the development of renal injury. Matrix metalloproteases (MMPs) have been shown to participate in renal fibrosis during DN. However, whether increases in GFR or hyperglycemia stimulate MMPs during DN remains to be determined. The current study determined the impact of elevations in RPP and/or hyperglycemia on MMP activity in Dahl salt‐sensitive (SS) rats. Experiments were performed on 6‐week old SS rats treated with either vehicle or streptozotocin (STZ, 50 mg/kg i.p.) to induce diabetes. After the induction of diabetes, both groups underwent surgery to place a silastic cuff on the aorta between the left and right kidneys to cause an increase in RPP to the right kidney by 10–20 mmHg: left kidney‐low RPP (110±3 mmHg) and right kidney‐high RPP (130±6 mmHg). After 3 weeks, blood glucose levels were markedly increased in the STZ‐treated rats versus vehicle rats (482±52 vs. 120±18 mg/dL, respectively). GFR was significantly elevated in response to both hyperglycemia and elevations in RPP compared to either hyperglycemia or elevated RPP alone. In comparison to the low RPP kidneys from the vehicle‐treated rats, proteinuria doubled in response to elevations in RPP alone (32±2 vs 16±8 μg/min) and increased by 4‐fold in response to both elevations in RPP and hyperglycemia (147±50 vs 16±8 μg/min, respectively). Renal MMP‐2 expression was 80% higher in response to elevations in RPP alone versus low RPP kidneys from vehicle rats. However, the effects of either hyperglycemia alone or in combination with increases in RPP on MMP‐2 expression were similar. Thus, these data suggest that the effects of elevations in RPP have a larger impact on renal MMP‐2 expression compared to either hyperglycemia alone or in combination with elevations in RPP.Support or Funding InformationThis research was supported by NIGMS NIH P20GM104357 and AHA 12SDG9440034.