bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporally‐Induced Nephron Polycystin‐1 Knockout Causes Salt and Water Wasting and Reduced Blood Pressure in the Absence of Polycystic Kidney Disease
Authors: Kohan Donald , Lakshmipathi Jayalakshmi , Stuart Deborah , Ramkumar Nirumpama , Gao Yang 
Published: June 2021

Polycystic kidney disease (PKD) is characterized by the early onset of hypertension that does not strictly correlate with cyst formation. Since deficiency of polycystin‐1 is the major cause of PKD, it may be that polycystin‐1 is directly involved in regulation of renal salt excretion and blood pressure regulation, i.e., it may exert physiological effects on kidney function independent of its involvement in cystogenesis. One previous study showed that distal nephron PC‐1 knockout caused fluid and electrolyte wasting, however these mice had dilated tubules, increased kidney size and increased renal cell proliferation, hence renal injury may have confounded findings. To address this, we administered doxycycline to Pax8‐rtTA/tetO7‐CMV*‐Cre/homozygous floxed Pkd1 mice at 3 months of age and studied the mice over the next 2–3 months. These mice demonstrated nephron‐specific Pkd1gene targeting. No cysts or tubule dilation were evident in any of the KO kidneys for at least 3 months after doxycycline administration. Food and water intake were similar between control (no doxycycline) and KO mice (same genotype as controls + doxycycline) on a normal, low and high Na+ intake (5–7 days each diet). Urine volume, urinary K+ excretion and urinary Na+ excretion were higher in KO vs. control mice during the first 2 days of high salt intake. Systolic and diastolic blood pressure were lower (by 4–5 mmHg) in KO mice during all diets. Plasma renin concentration was similar between control and KO mice on a normal Na+ diet and fell to the same degree in both genotypes on a high Na diet. Urinary endothelin‐1 and urinary nitrite/nitrate excretion were similar between control and KO mice on a normal Na+ diet and increased to the same degree in both genotypes on a high Na+ diet. KO mice had more rapid Na+ and K+ excretion following an acute intraperitoneal NaCl load and excreted more Na+ and K+ over the 7 hr following salt loading. Taken together, these data suggest that polycystin‐1 is involved in regulating renal electrolyte excretion in the absence of renal pathology. Surprisingly, nephron polycystin‐1 may exert a net Na+ and K+ retaining effect. Functional polycystin‐1 disruption in PKD does not appear to explain, independent of cyst formation, the hypertension observed early in the course of PKD.Support or Funding InformationNIH P01 HL136267This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
VEGF Therapy Shifts Macrophage Phenotype and Improves Renal Recovery in Chronic Kidney Disease
Authors: Engel Jason Edward , Guise Erika , Williams Maxx , Bidwell Gene , Chade Alejandro 
Published: June 2021

Chronic kidney disease (CKD) is universally associated with renal microvascular (MV) rarefaction and inflammation. We previously developed a fusion of rh‐vascular endothelial growth factor (VEGF) conjugated to an elastin like polypeptide (ELP) vector. We showed that ELP‐VEGF therapy is renoprotective in a model of unilateral renovascular disease (RVD). Here we test the hypothesis that ELP‐VEGF therapy in a novel model of CKD will recover renal function and MV rarefaction driven partly by modulation of renal macrophages to a pro‐angiogenic phenotype.CKD was induced in 10 pigs by bilateral RVD combined with diet‐induced hypercholesterolemia. After 6 weeks, pigs received a single intrarenal dose of ELP‐VEGF or placebo and were observed for 8 weeks. Renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified using multidetector computed tomography before, and 4 and 8 weeks after ELP‐VEGF therapy. Blood and urine were collected to quantify serum creatinine and albuminuria. Pigs were then euthanized and renal MV density, VEGF expression, and inflammation were quantified. Renal macrophage infiltration and phenotype was determined by concurrent staining for CD68, indoleamine 2,3 dioxygenase (IDO), and mannose receptor c type 1 (MRC1) (indicating total, M1, and M2 macrophages respectively). Further staining was performed to colocalize MRC1 and VEGF. An additional 5 pigs served as normal controls.RBF and GFR were reduced in all pigs at 6 weeks. ELP‐VEGF therapy induced a progressive recovery of RBF and GFR, accompanied by improved MV density, VEGF expression, and reduced albuminuria (1.8 ± 0.3 mg/dL vs. 2.9 ± 0.9 mg/dL in untreated CKD, p < 0.05) and creatinine (160 ± 10 μmol/L vs. 202 ± 16 μmol/L in untreated CKD, p < 0.05). Heavy IDO+/MRC1− pro‐inflammatory M1 macrophage infiltration was observed in untreated CKD and was shifted to a IDO−/MRC1+ anti‐inflammatory M2 phenotype after ELP‐VEGF therapy. Furthermore, augmented co‐expression of VEGF was observed in the MRC1+ renal macrophages (Figure).The progressive recovery of renal function far outlasted the life of administered ELP‐VEGF, suggesting that this single dose activates an endogenous mechanism of renal repair to sustain long term improvement. Accumulation of VEGF expressing M2 macrophages in the renal parenchyma may account for the recovery of MV rarefaction and renal hemodynamics after ELP‐VEGF treatment in CKD. These results suggest that modulation of macrophages towards a highly angiogenic M2 phenotype may constitute a prominent mechanism of renal recovery after ELP‐VEGF therapy in CKD.Support or Funding InformationSupport: HL95638, HL51971, GM104357, HL121527 (NIH), and EIA18490005 and IPA34170267 (AHA).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Kidney Specific Disruption of the Circadian Gene BMAL1 in Mice Produces a Sex‐ Dependent Effect on Systolic and Diastolic Blood Pressure
Authors: Glasford Krystal B , Crislip Gene Ryan , Douma Lauren G , Lynch Irma J , Cheng Kit‐Yan , Wingo Charles S , Gumz Michelle L 
Published: June 2021

IntroductionFluctuations in physiological functions that occur in all living organisms within a 24‐hour period are referred to as circadian rhythms. Disruptions in these rhythms are associated with cardiovascular diseases. A major goal of our lab is to find the link between circadian rhythms and cardiovascular health. Our internal clock is regulated by isoforms of four main transcriptions factors; PER, BMAL1, CLOCK and CRYPTOCHROME. Curtis et al., 2007, found that male global BMAL1 knockout mice have 10 mmHg lower blood pressure than control mice and lose their circadian rhythm. Our understanding of the regulation of circadian rhythms in blood pressure is incomplete. Thus, our objective was to investigate the effect of kidney specific BMAL1 knock out on the circadian rhythm of the diastolic blood pressure (DBP) and systolic blood pressure (SBP).HypothesisWe hypothesize that kidney‐specific BMAL1 knockout mice (KO) would lose their circadian rhythm of SBP and DBP.MethodsMouse models were generated using the Cre‐lox system. Telemeters were surgically inserted into the mice to continuously monitor blood pressure for 3 days. Blood pressure recordings were analyzed using Cosinor software to determine the MESOR, amplitude and period of the DBP and SBP data. The MESOR refers to the midline estimating statistic of rhythm which is a rhythm adjusted mean. The amplitude measures the extent of predictable change within a cycle and the period refers to the duration of a cycle, from peak to peak. WT and KO values were compared by t‐test.ResultsRefer to table 1 for MESOR, amplitude and period values. For SBP, male KO had significantly lower MESOR compared to WT (P=0.03). Similarly, for DBP, male KO had significantly lower MESOR compared to WT (P=0.04). For males, there were no significant differences in the amplitude or period of SBP or DBP. For females, there were no difference seen in the MESOR, amplitude or period for SBP or DBP.ConclusionOur data indicate that BMAL1 in the kidney does not contribute to circadian rhythms of blood pressure. However, BMAL1‐ dependent renal mechanisms contribute to a sex‐dependent effect on BP where only male KO experience lower mean arterial pressure compared to male WT.Support or Funding InformationAmerican Physiological Society Short‐ Term Research Education Program to Increase Diversity in Health Related Research (STRIDE); Gatorade Trust through the Department of Medicine; NIH grants R01 DK109570 (MLG), T32HL083810 (GRC) and T32DK104721 (LGD); National Heart, Lung and Blood Institute (Grant #1 R25 HL115473‐01)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prevention of Vascular Congestion Improves Renal Recovery and Function Post Renal Ischemia‐Reperfusion in Male Spontaneous Hypertensive Rats
Authors: Mohamed Riyaz , Crislip Gene Ryan , Ray Sarah , Wei Qingqing , O'Connor Paul M , Sullivan Jennifer C 
Published: June 2021

Acute kidney injury (AKI) due to ischemia‐reperfusion (IR) is a serious and frequent complication in clinical settings and often progresses to kidney failure. The male gender is associated with greater severity and mortality following AKI, and young males have a greater prevalence of hypertension vs. age‐matched females. Despite the widespread prevalence of hypertension as a common co‐morbid condition with AKI, the impact of established hypertension on the progression of renal injury post‐AKI in either sex is poorly understood. Vascular congestion in the outer medulla is an early event occurring after IR, and congestion has been linked to worse renal outcomes following IR. The present study tested the hypothesis that increased vascular congestion in hypertensive males leads to impaired renal recovery compared to hypertensive females following renal IR. 13 wk old male and female normotensive Sprague Dawley rats (SD) and Spontaneous Hypertensive Rats (SHR) were subjected to sham or 25‐minute warm bilateral ischemia followed by reperfusion (n=6). Blood and urine were collected at 24 hrs and 7 days after IR; kidneys were harvested at 7 days for histological analysis. IR increased plasma creatinine (Pcr), BUN and proteinuria in all groups compared to respective sham controls at 24 hrs, with a sex difference in IR‐induced increases in Pcr observed in SD but not in SHR (SD Scr: Psex*IR<0.05; SHR Pcr: Psex*IR=0.4). At 7 days post‐IR, Pcr and BUN remained elevated only in male SHR compared to sham control (Pcr: PIR=0.03; BUN: PIR<0.05); Pcr and BUN returned to sham levels in all other groups. Histological examination of SHR kidneys at 7 days post‐IR showed sustained increases in vascular congestion (PIR=0.01; Psex*IR=0.002), damaged tubules (PIR=0.0003; Psex*IR=0.0019) and tubular cell apoptosis (P IR=0.001; Psex*IR=0.001) compared to sham controls in male SHR but not in females. Further, to study the role of IR induced vascular congestion on impaired recovery and loss of renal function in male SHR, additional SHR were pretreated with heparin (1500U/kg, n=6) prior to IR. Pre‐treatment with heparin prevented IR‐induced vascular congestion (PIR*Heparin=0.04) and tubular damage (PIR*Heparin=0.02) and improved renal function in male SHR 7 days post‐IR (Scr‐PIR*Heparin<0.05; BUN: PIR*Heparin=0.02) compared to heparin treated sham controls. Heparin pretreatment did not alter kidney function in female SHR 7 days post‐IR (Pcr‐PIR*Heparin=0.9; BUN: PIR*Heparin=0.2). In conclusion, our data demonstrated that persistent IR‐induced vascular congestion is a major driving factor to long‐term impaired renal recovery post IR in hypertensive males.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex‐Differences in Renal Na+ Regulatory Mechanisms During Acclimation to a High Salt Diet
Authors: Gohar Eman Y. , De Miguel Carmen , Obi Ijeoma E. , Daugherty Elizabeth M. , Becker Bryan K. , Jin Chunhua , Johnston Jermaine G. , Liu Pengyuan , Speed Joshua S. , Mitchell Tanecia , Kriegel Alison , Pollock Jennifer S. , Pollock David M. 
Published: June 2021

Hypertension is more prevalent in men compared to premenopausal women. Maintenance of Na+ homeostasis is an essential component of blood pressure regulation, and defects in the renal capacity to appropriately excrete Na+ are fundamental mechanisms involved in the initiation of salt‐sensitive hypertension. We recently reported that female rats elicit a more rapid natriuretic response to a high salt (HS) diet compared to males. The overall goal of the current study was to determine the natriuretic signaling pathway(s) involved in the enhanced ability of females to handle HS challenges. Male and female Sprague Dawley rats (16–18 weeks old) were placed into metabolic cages on normal salt (NS, 0.49% NaCl) followed by HS (4% NaCl) diet for 5 days. 24‐hour urine samples were assessed for endothelin‐1 (ET‐1), aldosterone (ALD) and norepinephrine (NE). On NS, urinary ET‐1 was significantly higher in females, compared to males; no sex‐differences were detected in urinary ALD or NE. In males, urinary ET‐1 was increased (10.2±0.8 vs. 5.6±1.0 pg/kg/day, n=8 each, p=0.002) and urinary ALD was decreased on day 1 HS relative to NS (6.1±0.7 vs. 15.2±2.6 μg/kg/day, n=5 each, p=0.02); no significant changes were observed in ET‐1 or ALD in females on day 1 HS. Urinary NE remained unchanged during the HS challenge in both sexes. Ingenuity Pathway Analysis (IPA) of RNA sequencing data from inner medullae from males and females on NS identified an enrichment (p=3.11E‐04) of transcripts in the ET‐1 signaling pathway in females, with the abundance of 35/190 (18.4%) of pathway transcripts being at least 1.5‐fold different in abundance between sexes. Further, IPA predicted that ET‐1 signaling is activated in female inner medulla, relative to males. Previous studies showed that interleukin‐1β (IL‐1β) stimulates renal ET‐1 production. Thus we tested whether renal IL‐1β is upregulated in response to HS in a sex‐dependent manner. Renal IL‐1β was assessed by ELISA and IHC. Renal cortical IL‐1β was significantly increased on day 1 HS, relative to NS, only in males (8.1±0.3 vs. 6.4±0.3 pg/mg protein, n=9 each, p=0.03). Our data suggest that activation of IL‐1β/ET‐1 and inhibition of ALD signaling pathways contribute to acclimation to HS challenges in males. We further suggest that the already activated renal ET‐1 signaling in females under NS may contribute to the enhanced ability to acclimate to HS challenges observed in females.Support or Funding InformationFunded by AHA 18CDA34110010 and 15POST25090329 to EYG, and P01 HL136267 to JSP and DMP. We appreciate Drs. Celso and Elise Gomez‐Sanchez's help with ALD assay.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Salt Diet Induces HDAC1‐Dependent Disruption of Nitric Oxide Signaling in the Renal Microvasculature
Authors: Dunaway Luke S , Cook Anthony K , Pollock David M , Hyndman Kelly A , Inscho Edward W , Pollock Jennifer S 
Published: June 2021

Our lab previously reported that in cultured endothelial cells, histone deacetylase 1 (HDAC1) mediates reduced endothelial nitric oxide synthase (NOS3)‐derived NO production and decreased lysine acetylation of NOS3. Recently, we also observed that a high salt diet (HS) increases expression of HDAC1 in the kidney. The objectives of this study were: 1) to test the hypothesis that HS increases HDAC1 abundance or activity in intra‐renal resistance arteries, and, 2) to test the hypothesis that HS mediates HDAC1‐dependent loss of NO signaling in the vasculature. We isolated intra‐renal arteries from male Sprague Dawley rats fed either normal salt diet (NS; 0.49% NaCl) or 2 weeks of HS (4.0% NaCl). HDAC activity was increased as detected by a decrease in histone H3 lysine acetylation status (NS: 1.0 ± 0.033 RDU vs HS: 0.56 ± 0.096 RDU, n=3, p<0.05). This change in HDAC activity was not due to changes in abundance of Class I HDACs: HDAC1 (NS: 1.0 ± 0.11 RDU vs HS: 1.19 ± 0.15 RDU, n=5–8, p>0.05), HDAC2 (NS: 1.0 ± 0.25 RDU vs HS: 1.17 ± 0.13 RDU, n=3–5, p>0.05), HDAC3 (NS: 1.0 ± 0.21 RDU vs HS: 0.99 ± 0.13 RDU, n=3–5, p>0.05), and HDAC8 (NS: 1.0 ± 0.07 RDU vs HS: 0.94 ± .07 RDU, n=3–5, p>0.05). To test the second hypothesis, rat afferent arteriolar vasoconstrictor responses to the NOS inhibitor, LNAME, were monitored using the in vitro, blood perfused juxtamedullary nephron preparation. Arterioles from HS fed rats had significantly blunted L‐NAME‐induced vasoconstriction compared to vehicle treated arterioles from NS fed rats (96 ± 2% of Con vs 76 ± 2% of Con for HS vs. NS; respectively, P<0.05); however, HDAC1 inhibition with 300 nM MS‐275 restored the arteriolar constrictor responses in HS rats (79 ± 3% of Con) to be similar to NS fed rats (P>0.05) and to NS rats + MS‐275 (79 ± 1% of Con; P>0.05). These findings support our hypothesis that HDAC1 regulates NO‐dependent signaling in the renal microvasculature.Support or Funding InformationSupported by T32 GM 109780‐3 to LSD, K01 DK105038 to KAH, P01 HL069999 to JSP and DMP, and P01 HL136267 to JSP, EWI, and DMP.This 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 Two Creatine Monohydrate Feeding Protocols on Doxorubicin‐Induced Skeletal Muscle Dysfunction
Authors: Torok Zoltan A , Busekrus Raquel B , Hydock David 
Published: June 2021

The chemotherapy drug doxorubicin (Dox) can negatively impact skeletal muscle function, and interventions to address this side effect are important to improving cancer patient quality of life. The purpose of this study was to investigate the effects of creatine monohydrate (Cr) feeding prior to Dox treatment on skeletal muscle function. Male Sprague‐Dawley rats were randomly assigned to one of four groups: standard chow feeding for four weeks followed by a bolus i.p. 15 mg/kg Dox injection (Dox group); 2% Cr chow feeding for four weeks followed by a bolus i.p. 15 mg/kg Dox injection (Cr1+Dox group); 4% Cr chow feeding for one week then 2% Cr chow feeding for three weeks followed by a bolus i.p. 15 mg/kg Dox injection (Cr2+Dox group); or standard chow feeding for four weeks followed by a bolus i.p. 0.9% NaCl injection to act as a control (Con group). Grip force measurements were obtained prior to the start of nutritional interventions (baseline), prior to injection (after four‐week nutritional intervention), and three days post‐injection. Animals were anesthetized three days post‐injection, the soleus (SOL) and extensor digitorum longus (EDL) muscles were excised, and function was assessed ex vivo using a 100 second fatigue protocol. No grip force differences were observed at baseline or following the four‐week nutritional interventions. Three days after injections, however, the Dox and Cr1+Dox groups had lower grip forces than Con (p<0.05), but this difference was not observed in Cr2+Dox (p>0.05). In the SOL, no between group force differences were observed at baseline or at any of the 10 second time points throughout the fatigue protocol (p>0.05). EDLs from the Dox group generated significantly less force than Con throughout the protocol except the 50 s and 60 s time points (p<0.05). These differences in EDL force production throughout the protocol, however, were not observed in Cr1+Dox and Cr2+Dox (p>0.05). In conclusion, Cr1 and Cr2 feeding protected against Dox‐induced declines in force production in the type II, EDL muscle, and grip force was preserved only with Cr2 feeding. These results suggest that Cr's protection against Dox myotoxicity may be dependent upon Cr dose and skeletal muscle type.Support or Funding InformationDavid S. Hydock, PhD was supported by a Pilot and Exploratory Projects in Palliative Care of Cancer Patients and Their Families, PEP‐17‐193‐01 ‐ PCSM, from the American Cancer Society.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fasting Regulation of Muscle Autophagy during Cancer‐Cachexia
Authors: Fix Dennis , Counts Brittany , VanderVeen Brandon , Carson James A. 
Published: June 2021

IntroductionCancer cachexia is a characterized by accelerated skeletal muscle protein turnover that contributes to muscle mass loss. The adenosine monophosphate protein kinase (AMPK) is cellular energy sensor that is activated in response to energy stress and regulates the initiation of autophagy. The autophagy process involves lysosomal removal of cellular organelles and protein aggregates through sequestration of cytosolic substrates and tagging with ubiquination‐linked proteins such as LC3 and P62. While our understanding of AMPK's role in suppressed protein synthesis during cancer cachexia has improved, the regulation of autophagic processes by AMPK during cancer cachexia requires additional work. The purpose of this study is to examine the effect of nutrient deprivation on AMPK activation and autophagy initiation during cancer cachexia.MethodsMale C57BL/6 (B6, N=16) and ApcMin/+ (Min, N=18) mice were subjected to a 12 hour fast. B6 and Min mice fed ad‐libitum served as controls. Following the 12‐hour fast, hindlimb muscles were harvested and the gastrocnemius homogenized for protein analysis.ResultsMin mice exhibited body weight loss and reduced gastrocnemius mass when compared to B6 mice. In the fed state muscle AMPK phosphorylation (T172) was induced in the Min compared to B6. Fasting did not induce AMPK phosphorylation in B6 mice; however, AMPK was induced in Min mice following a fast. AKT phosphorylation (T308) was reduced following a fast in both B6 and Min mice. Furthermore, fasting suppressed FOXO1 phosphorylation in Min mice, similarly to B6 mice. However, fasted MIN mice had a reduction in P62 expression and an induction of LC3 II/I protein expression not seen in fasted B6 mice.ConclusionsTaken together our results suggest that cachectic skeletal muscle has increased sensitivity to acute nutrient deprivation demonstrated by AMPK activation and the initiation of autophagy when compared to healthy adult skeletal muscle.Support or Funding InformationThis work was supported by NIH/NCI grant RO1CA121249 awarded to James A. CarsonThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.