bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inner Medullary Urea Transporters Contribute to Development of Renal Fibrosis in Mice With Unilateral Ureteral Obstruction
Authors: Rianto Fitra , Ellis Carla L , Hassounah Faten , Wang Xiaonan H. , Klein Janet D. , Sands Jeff M. 
Published: June 2021

Fourteen percent of the population of the United States is affected by chronic kidney disease (CKD). Although the mechanisms that are responsible for CKD remain unclear, there are many clinical and animal studies showing that low protein diets reduce the long term effects of CKD. One possible explanation for these benefits is the restricted urea load of the low protein diet suggesting a role for the urea transporters in this process. Unilateral ureteral obstruction (UUO) is a well known model to produce fibrogenic responses such as increased capillary macrophages, pro‐fibrogenic proteins, interstitial matrix, myofibroblasts, etc. in CKD rodents. We hypothesized that the urea transporters contribute to the development of renal fibrosis. We used UUO mice receiving a maximal urea load (high protein diet) to investigate contributions of urea transporters to renal fibrosis. C57Bl6 mice ± genetic ablation of UT‐A1 and UT‐A3 urea transporters (UT‐A1/A3 KO) underwent UUO surgery (ligation of the left proximal ureter). Four days after surgery mice were given a high (40%) protein diet for 10 further days. Mice were killed and obstructed kidneys collected for protein and histochemical analysis. All of the obstructed kidneys showed evidence of hydronephrosis after 14 days. BUN was unchanged by UUO: WT control: 44.2 mg/dl, WT UUO: 46.8 mg/dl, KO control: 43.4, KO UUO: 47.1. TGF‐b was increased in both WT and UT‐A1/A3 KO mice with UUO (302% and 389% respectively). WT with UUO showed a 320% increase in α‐SMA vs mice without UUO. UT‐A1/A3 KO mice with UUO showed a blunted 271% increase in α‐SMA vs unobstructed UT‐A1/A3 KO mice. Vimentin, another marker of fibrosis, was significantly increased 555% by UUO (vs no UUO). UUO in UT‐A1/A3 KO mice did not increase vimentin. H&E staining revealed similar infiltration of inflammatory cells in both UUO WT and UUO UT‐A1/A3 KO mice. Trichrome staining showed higher collagen levels in UUO WT vs UUO UT‐A1/A3 KO mice. Immunohistochemical staining for αSMA and vimentin revealed higher levels in UUO WT vs UUO UT‐A1/A3 KO mice. These data suggest that urea transporters do not prevent inflammation caused by UUO. However, the overall development of fibrosis in UUO mice fed a high protein diet is attenuated by the absence of urea transporters suggesting that urea reabsorption by urea transporters contributes to renal fibrosis. If urea transport inhibitors replicate the effects of genetic knock out, they may represent a promising future therapy.Support or Funding InformationRelypsa Nephrology and Cardiology Fellowship Grant;NIH RO1 DK41707This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypogonadal Hypertension in Male Sprague‐Dawley Rats Is Reversed by Testosterone Replacement Therapy, which Suppresses Renin‐Angiotensin System Expression
Authors: Hanson Andrea E. , Garcia Nikolas W. , McKenna Joshua M. , Perusquia Mercedes , Stallone John N. 
Published: June 2021

Testosterone (TES) and other androgens are efficacious vasodilators acutely, both in vitro and in vivo; however, their long‐term effects on arterial blood pressure (BP) are unclear. We previously reported that castration (CsX) produced hypertension in normal male rats, and that TES replacement therapy (TRT) was antihypertensive and normalized BP. Thus, long‐term effects of endogenous TES and exogenous TRT on BP and renin‐angiotensin system (RAS) function were studied in intact (InT) and castrated (CsX) male Sprague‐Dawley (SD) and Testicular‐feminized male (Tfm, androgen receptor defective) rats (12–13 wk old). Weekly measurements of systolic BP (tail cuff plethysmography) revealed a progressive rise in BP over 10 wks in CsX (108 ± 0.9 vs. 139 ± 1.2 mmHg), while BP remained stable in InT (109 ± 3.1 vs. 115 ± 0.5). During the next 5 weeks, half of CsX received TRT (CsX+TES‐enanthate‐replaced; 1.75 mg/kg, 2X/wk). BP gradually declined to normal in CsX+TES replaced rats (115 ± 1.2), while BP remained elevated in CsX (141 ± 1.2) and normal in InT (113 ± 0.3). In separate CsX‐SD rats, treatment with Losartan (LST; 250 mg/L drinking water) prevented development of hypertension at 10 wks (95 ± 0.8 CsX+LST vs. 139 ± 1.2 in CsX). During the next 5 weeks with TRT, BP declined in CsX+TES (113 ± 1.3) and remained lower in CsX+LST (99 ± 0.4). In Tfm, CsX resulted in a similar rise in BP (108 ± 0.6 vs. 139 ± 0.4 mmHg), and TRT reduced BP to a similar extent (106 ± 1.5). Real‐time PCR (rt‐PCR) of kidney from InT, CsX, and CsX+TES rats revealed that CsX increased expression of renin (45.5%), AT1 receptor (AT1R; 38%), and angiotensin converting enzyme (ACE; 239%) mRNA, while TRT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. In contrast, CsX reduced expression of angiotensinogen (Angt) mRNA (59%) while TRT restored Angt mRNA to 78% of InT rats. 24 hr urine output (UO) in InT‐SD was 48.3 ml/kg at baseline, 34.3 at 10 wks, 38.4 at 12 wks, and 34.8 at 15 wks. UO in CsX‐SD was 47.6, 30.3, 25.2, and 27.7; UO in CsX+TRT was 46.1, 29.2 36.2, and 29.5. These data suggest that: 1) endogenous androgens (TES) exert antihypertensive effects in male SD and Tfm rats; 2) the antihypertensive effect of TES appear to involve a diuretic effect on the kidney, which is non‐genomically mediated; and 3) these antihypertensive effects may involve TES‐induced reductions in RAS expression in the kidney.Support or Funding InformationState of TexasThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fecal Bypass Macronutrients Impact Stool Quality in Dogs and Cats while Species Differentially Impacts Nutrient Digestibility
Authors: Jackson Matthew Irick , Wernimont Susan M. , Carnagey Kristen , Jewell Dennis E. 
Published: June 2021

ObjectivesEvaluate the impact of animal and food characteristics on apparent digestibility and stool quality in dogs and cats.MethodsHealthy dogs and cats were housed in environments promoting social interaction, having access to natural light that varied with season and opportunity to exercise. Animals were fed to maintain healthy body weight and health was monitored through regular clinical and physical checkups. Across two decades, 11,963 studies examining apparent nutrient digestibility were conducted using dry and canned foods. Studies were carried out under IACUC approved protocols. Proportional digestibility for dry matter, fat, nitrogen‐free extract, and fiber was calculated as difference between analyzed amounts in the food versus feces. Stool quality was evaluated using a standardized 5‐point system. Relations between animal characteristics (age, stool quality) and digestibility, as well as interactions between macronutrients that bypassed digestion, were evaluated with linear mixed models. Results significant at p≤0.05 are reported.ResultsIn dogs, there was a negative association between age and linear coefficients for fiber, dry matter, carbohydrate, and fat digestibility but a positive association between age and quadratic coefficients for carbohydrate and dry matter digestibility. In cats, there was positive association between age and linear coefficients for protein and energy while there were negative associations between age and the linear coefficient for fiber and the quadratic coefficient for protein. Maximum protein digestibility occurred at approximately 14 years in dogs and at 8 years in cats; maximum crude fiber digestibility in dogs and cats occurred at 1 year. In both species, high fecal protein and low fecal fiber predicted decreased stool quality, and fecal fiber was positively associated with fecal protein and fat.ConclusionsAging in dogs and cats differentially impacted nutrient digestibility; protein and energy digestibility had a positive linear association with age in cats, while dry matter, carbohydrate, energy and fat digestibility had a negative linear association with age in dogs. In both species, fiber digestibility linearly decreased with increasing age. Undigested fecal fiber was associated with improved stool quality while fecal protein was detrimental. Intriguingly, the impact of fecal bypass macronutrients on stool quality was significantly greater in cats than dogs. This is the largest investigation to date evaluating associations between age and macronutrient digestibility in dogs and cats, and supports the development of diets to optimize health throughout the lifespan.Support or Funding InformationHill's Pet Nutrition, Inc. Topeka, Kansas, USAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of a Probiotic and a Specifically Immunized Egg Powder on Sleep and Overall Health, Well‐being, and Gastrointestinal Symptoms in a Subclinical Population
Authors: Trigg Dorothy , Shaw Rachael , Asad Taheya , Jones Ashleigh , Skelton Michele 
Published: June 2021

The purpose of this study was to examine the effects of a specifically immunized egg powder taken with a probiotic on sleep quality and patterns of sleep using the Pittsburgh Sleep Quality Index (PSQI) and health related quality of life as it applies to the gastrointestinal tract using the Gastrointestinal Quality of Life Index (GIQLI) in healthy subjects with subclinical GI complaints. In a randomized, double‐blind placebo‐controlled study, sixteen subjects were divided into two groups. One group received a probiotic plus 2 grams of a specifically immunized egg powder (treatment group) while the other group received a placebo. The PSQI and GIQLI were given to subjects prior to supplementation and immediately after a 4‐week supplementation phase. There were no significant differences in PSQI scores between groups. However, a significant improvement in sleep quality was measured in the treatment group (p < 0.05). There were no significant differences in GIQLI scores between groups. However, a significant improvement in the physical subset score of the GIQLI was measured in the treatment group (p < 0.05). Additionally, there was a strong statistical trend for improvement in the social subset score of the GIQLI and the total score on the GIQLI in the treatment group (p < 0.06). Preliminary analysis suggests that a combination of a probiotic and a specifically immunized egg powder may contribute to improved sleep and overall gastrointestinal health and well‐being in healthy subjects with subclinical GI complaints.Support or Funding InformationIgY NutritionThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of 6‐weeks of Time‐Restricted Feeding in Normal Weight Middle‐Aged and Older Adults
Authors: Nagy Erzsebet E , Rossman Matthew J , Mazzo Melissa R , Denman Blair A , Jankowski Lindsey R , Richey James J , Johnson Sarah A , Wang Yang , Peterson Courtney M , Chonchol Michel B , Seals Douglas R , Martens Christopher R 
Published: June 2021

Calorie restriction (CR) improves multiple indicators of healthspan and physiological function in humans. However, CR is contraindicated in normal‐weight middle‐aged and older (MA/O) adults because it induces deleterious adaptations, such as reductions in body mass (including skeletal muscle mass) and bone mineral density (BMD). Time‐restricted feeding (TRF), which involves consuming all calories within an 8–10‐hour window and fasting for the remainder of the day, has the potential to maximize the benefits of CR while minimizing these possible adverse effects in normal‐weight MA/O adults. We performed a randomized controlled crossover clinical trial to evaluate the feasibility, tolerability and lack of adverse changes in body composition and BMD following six weeks of TRF vs. normal feeding (NF) in normal‐weight MA/O adult men and women (n=22, 67±6 years). A secondary aim was to explore the potential efficacy of TRF for improving select indices of healthspan and physiological function. Adherence to TRF was excellent with all subjects successfully reducing their eating window from 11.7 ± 0.3 hours/day to within 8 hours/day (7.6±0.1 hours/day, p<0.05). Compared with NF, all subjects maintained their regular daily energy intake during TRF, with no significant changes in macronutrient composition or overall diet quality, as assessed using the Healthy Eating Index (HEI; NF= 63±3 vs. TRF= 61±2, p>0.05). TRF was well‐tolerated with no increases in self‐reported desire to eat, satiety, or stomach fullness (all p>0.05 vs. NF) and interestingly, lower feelings of hunger (p<0.01 vs. NF). Importantly, TRF did not affect body mass, BMD or body composition (all p>0.05 vs. NF). TRF improved two indices of cardiorespiratory fitness, including a reduced heart rate during submaximal exercise (p<0.05) and increased distance traveled during a 6‐minute walk test (NF=570±12 m vs. TRF=585±11 m, p<0.05). Glucose tolerance, assessed during a 2‐hour oral glucose tolerance test in a subset of subjects (n=16), also improved with TRF (NF=15,500±300 mg/dL x min vs. TRF=14,500±200 mg/dL x min, p<0.05). These findings suggest that TRF is feasible and well‐tolerated in normal‐weight MA/O adults and is not associated with adverse changes in body composition or BMD. Moreover, TRF may improve cardiorespiratory fitness and glycemic control, two important indicators of healthspan and future risk of chronic disease, disability, and/or frailty. Thus, TRF may be a practical alternative to conventional CR for improving healthspan in normal‐weight MA/O adults.Support or Funding InformationSupported by Aging T32 AG000279This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Unexpected Lethal Consequences of Disrupting Angiotensinogen in Agouti‐Related Peptide (AgRP)‐Expressing Cells
Authors: Sapouckey Sarah A , Deng Guorui , Pearson Nicole A , Gibson‐Corley Katherine N , Grobe Justin L 
Published: June 2021

Genetic disruption of angiotensin (ANG) type 1A receptors (AT1A) in cells which express Agouti‐related peptide (AgRP) abolishes thermogenic sympathetic nerve activity (SNA) and resting metabolic rate (RMR) responses to leptin and high fat diet (HFD). Although it is known that glia secrete angiotensinogen (AGT), in silico reanalysis of published single‐cell RNAseq datasets describing transcriptomes of cells from mouse hypothalamus (GSE74672) and RNAscope fluorescent in situ hybridization independently confirm that AgRP neurons of the hypothalamic arcuate nucleus (ARC) in adult wildtype mice express AGT mRNA. We therefore sought to explore the functional significance of this expression pattern. Why, if AgRP neurons are bathed in AGT in the interstitial space, would they synthesize AGT? Mice were generated which lack AGT specifically in AgRP cells (AGTAgRP‐KO mice) using the Cre‐Lox approach (sire: AgRP‐Cre+, AGTF/WT x dam: AgRP‐Cre−, AGTF/F). Of the first 116 offspring, this resulted in expected overall distributions across sex (53% female), Cre (47% Cre+) and AGT (46% AGTF/F) genotypes, but an underrepresentation of targeted AGTAgRP‐KO mice at weaning (n=5 females + 1 male; Χ2=52.0, df=3, p<0.001), suggesting pre‐weaning or in utero lethality of the genotype. Before and at 8 weeks of age, female AGTAgRP‐KO mice exhibited normal body mass (n=5, 17.3±0.4 vs n=12 littermates 17.3±0.3 g); 5 weeks of 45% HFD caused significant weight gain in all mice (p<0.05), but AGTAgRP‐KO mice gained less (body mass: 18.3±0.4 vs 19.7±0.3 g, p<0.05, and fat mass by NMR: 1.6±0.4 vs 2.3±0.2 g, p<0.05), which was not due to suppression of food intake (p=NS) or digestive efficiency as assessed by bomb calorimetry (p=NS). Histological examination of the kidney suggests the presence of interstitial fibrosis, inflammation, glomerulosclerosis and tubular dilation in AGTAgRP‐KO mice. Interestingly, Cre activity is present within the medulla of both the adrenal gland and kidney but not liver of AgRP‐Cre mice. Preliminary tests suggest reduced total aldosterone (n=5, 3.6±1.7 vs n=9 littermates 6.9±1.1 ng/d) and corticosterone (n=6, 0.4±0.1 pg vs n=9 littermates 0.9±0.2 ng/d) in the urine, but no changes in AGT gene expression in the liver or kidney (n=3,4 p=NS) of AGTAgRP‐KO mice. We conclude that (i) AGT is expressed by AgRP cells of the ARC, (ii) the AgRP‐Cre construct drives Cre activity in these cells, but also in layers of the adrenal gland and kidney, (iii) disruption of AGT in cells targeted by AgRP‐Cre unexpectedly causes a developmental lethality that is more penetrant in males, and (iv) in surviving females, the disruption of AGT in AgRP‐expressing cells causes resistance to weight gain through increased energy expenditure.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hybrid Rat Diversity Program (HRDP): A Rat Resource for Systems Genetics
Authors: Dwinell Melinda , Takizawa Akiko , Lazcares Lynn , Saba Laura , Tabakoff Boris , Shimoyama Mary 
Published: June 2021

Genetic susceptibility to disease, sensitivity to environmental elements, and pharmacogenomics are critical components of the concepts of precision medicine. Rats are a major model for studying complex disease mechanisms, behavioral phenotypes, environmental factors, and for drug development and discovery. Inbred rat strains control for genetic background and allow for repeated, reproducible molecular, cellular, and whole animal phenotyping. Through the development of the Hybrid Rat Diversity Program, a powerful panel of inbred rats with genomic, physiologic, and behavioral phenotype data will serve as a catalyst for research in many fields. The Hybrid Rat Diversity Panel (HRDP) will consist of 96 inbred rat strains to maximize power to detect specific genetic loci associated with complex traits while maximizing the genetic diversity among strains. The 96 strain panel consists of 33 genetically diverse inbred strains and two panels of recombinant inbred panels: FXLE/LEXF (33 strains, Japan) and HXB/BXH (30 strains, Czech Republic). Embryo resuscitation and breeding are underway at the Medical College of Wisconsin (MCW). Whole genome sequencing for all 96 strains will be performed by the Genomic Sciences and Precision Medicine Center (MCW) sequencing core to achieve 30X coverage (Illumina NovaSeq S4). Liver and brain transcriptome analysis will be done for the entire HRDP panel through PhenoGen (http://phenogen.ucdenver.edu) at the University of Colorado (Tabakoff and Saba). Genomic, phenotype, and strain information will be made available through the Hybrid Rat Diversity Panel portal at the Rat Genome Database (http://rgd.mcw.edu). MCW will partner with the Rat Resource & Research Center (RRRC, http://www.rrrc.us) at the University of Missouri for strain distribution. The HRDP will provide a genetically stable population of rat strains with fully sequenced genomes, transcriptomes for brain and liver, and general phenotypic characterization to be used for systems genetic studies and fine mapping of complex traits.Support or Funding InformationNational Institutes of Health, Office of the Director, R24OD024617This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Reexamination of Breast Cancer Gene Expression Data Using (and Comparing) Advanced Predictive Modeling Techniques
Authors: Hummel Ruth M , Genung Daniel 
Published: June 2021

Using the human breast cancer data from the MAQC‐II Project (GEO Accession GSE20194), we re‐explore the association between gene expression and Estrogen Receptor Status across advancing stages of the disease. We specifically compare various predictive modeling techniques, such as Radial Basis Machines and Partition Trees, as well as various predictor reduction techniques, including K‐Means Clustering and LASSO, and we discuss the merits of each. We use k‐fold cross‐validation to improve upon a simple single training/validation split in comparison of model performance and consistency.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dysregulation of metalloproteinase complex ADAM10‐MMP14 plays the key role in preservation of adherens junction integrity at renal cystogenesis
Authors: Xu Frank , Kong Tianqing , Lu Tzongshi 
Published: June 2021

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common lifeth‐reatening genetic diseases and is characterized by early cystogenesis in kidney, which eventually results in end‐stage renal disease. We previously reported that the inhibition of A Disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) can block the cystogenesis in renal tubular epithelial cells through the preservation of E‐Cadherin. In addition, recent studies also indicate that another major matrix metalloproteinase, Matrix metalloproteinase‐14 (MMP14) promotes cystogenesis in kidney epithelial cells, which was blocked by its inhibitors. In our study, we investigate these two major sheddases association and their roles in preservation of adherens junctions in renal cystogenesisMethodsImmunoprecipitation, immunostaining and 3‐D cell culture technologies are used to analyze the interaction between metalloproteinase ADAM10 and MMP14 in Madin‐Darby Canine Kidney (MDCK) cells.ResultsOur data shows that ADAM10 and MMP14 form a stable complex on the membrane of MDCK cells at hemopexin domain of MMP14. The activation of MMP14 is required for ADAM10 in shedding of E‐Cadherin. Either an enzyme‐inactive mutant MMP14E240A (Glu240 to Ala) or the deletion of the catalytic domain of MMP14 (MMP14ΔCAT) significantly decreases the sheddase activity of ADAM10. In addition, knockdown of MMP14 decreases the cleavage of ECadherin by ADAM10, and knockdown of ADAM10 enhances the activation of proMMP2 by MMP14. Furthermore, ectopic expression of MMP14 increases the proliferation of renal epithelial cells, alters the cell‐cell adhesion and promotes the cystogenesis of renal epithelial cells in 3‐dimensional collagen‐1 gels. Ectopic expression of the MMP14E240A mutant promotes strong contact inhibition of the cells, and results in tubular rather than cystic growth in collagen gels.ConclusionOur study shows for the first time that ADAM10 form a unique, stable complex at hemopexin domain of MMP14 on the surface of epithelial cells, and the ADAM10‐MMP14 complex regulates their sheddase activity on many cell junctional proteins. Furthermore, ADAM10 is a negative regulator of MMP14 that ADAM10 inhibits the shaddase activity of MMP14. The functional interaction between ADAM10 and MMP14 as a complex could play a pivotal role in the cystogenesis of renal epithelial cells. Our data provide a potential therapeutic target in ADPKD through the modulation of ADAM10‐MMP14 complex.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.