bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sympathomodulation in heart failure: A role for stellate ganglia Nrf2
Authors: Shanks Julia , Gao Lie , Zucker Irving H. 
Published: June 2021

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a key transcription factor involved in modulating redox signalling by regulating the expression of a number of antioxidant genes. It is known that both sympathetic hyperactivity and increased oxidative signalling are hallmarks of chronic heart failure (HF). Previous data from our group have shown that site selective deletion of Nrf2 in the rostral ventrolateral medulla (RVLM) increases blood pressure, reduces baroreflex sensitivity and increases renal sympathetic nerve activity (RSNA) in normotensive mice. Moreover, Nrf2 expression is downregulated in the RVLM of HF mice, where its selective viral up regulation improves baroreflex sensitivity and reduces sympathetic tone. In this study we hypothesized that Nrf2 expression is downregulated in all sympathetic neural tissue in HF, and that selective overexpression of Nrf2 in the stellate ganglia would suppress cardiac sympatho‐hyperactivity and arrhythmogenesis in HF. Heart failure was induced by coronary artery ligation in both mice and rats. Terminal experiments were performed 6 weeks post MI. Heart failure was confirmed by echocardiography. Nrf2 protein and message expression were determined by western blot and rt‐PCR, respectively. Markers of oxidative stress within the stellate were determined using a variety of immunofluorescent techniques. Acute terminal experiments (2 % isoflurane) in rats, determined haemodynamic changes to stellate stimulation. Expression of Nrf2 protein and message was significantly down regulated within the stellate ganglia of both male and female mice (Nrf2 Protein: Male‐Sham, 0.65 ± 0.08 (n = 10), Male‐HF, 0.29 ± 0.13 (n = 9), p < 0.01. Female‐Sham, 0.53 ± 0.05 (n = 3), Female‐HF, 0.25 ± 0.04 (n = 3), ratio Nrf2/GAPDH). Nrf2 mRNA: Male‐Sham, 0.98 ± 0.03 (n = 2), Male‐HF, 0.49 ± 0.55 (n = 3), p < 0.05). Increased markers of redox signalling were seen within the stellate ganglia of HF mice, including increased labelling for 3‐Nitrosylation (3‐NT), 4 Hydroxynonenal, 8‐OHdG, and DHE as a marker of superoxide production. We also observed a reduction in Nrf2, and its downstream target NQO1 in the stellate ganglia of HF rats (10 weeks post coronary artery ligation (2% isoflurane), n = 5, sham and HF), a reduction in stellate Nrf2 was correlated with infarct size and ejection fraction. Within the HF group we observed increased haemodynamic changes to stellate stimulation in anaesthetized rats. These data suggest that oxidative signalling is increased and Nrf2 reduced within the stellate ganglia in HF and could open the potential for future therapeutic targets. Upregulation of Nrf2 in the stellate ganglia and the role of stellate ganglia Nrf2 in cardiac sympathetic drive and redox signalling in HF remain to be determined.Support or Funding InformationWork done with support of the NIH (PO‐1 HL62222) and AHA (18POST34030046).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glut5‐KD reduces blood pressure via increases phosphorylation of nNOS and decreases NADPH oxidase by AMPK activation in the NTS of fructose‐induced hypertensive rats
Authors: Chen Hsin‐Hung , Cheng Pei‐Wen , Tseng Ching‐Jiunn 
Published: June 2021

Glucose transporter5 (GLUT5) is a fructose transporter in enterocytes. Many studies indicated that the mechanisms by which excessive fructose increases blood pressure. GLUT5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the nucleus tractus solitarii (NTS). The aim of this study was to investigate whether knock‐down GLUT5 in the NTS can improve hypertension in fructose‐fed rats with 10% fructose water. Our in vivo study showed that GLUT1/5 mRNA levels increased in the NTS of fructose‐fed rats at the early stage of 7 days. Our in vitro immunoblotting study found that fructose‐induced GLUT5 up‐regulated lead to AKT‐nNOS signaling pathway significantly decreased in PC12 neuronal cells after fructose treatment. In addition, we injected lentivirus‐delivered GLUT5 shRNA into the NTS of fructose‐induced hypertensive rats for 6 weeks. Two weeks after injection of lentivirus‐delivered GLUT5 shRNA, we fed with 10% fructose water for 4 weeks. Glut5‐knockdown (KD) down‐regulates blood pressure through improved sympathetic hyperactivity and central insulin signaling in the fructose‐induced hypertensive rats. Our data showed that Glut5‐KD restores AMPK‐dependent mechanism, decreases fructose‐induced oxidative stress, which attenuated NADPH oxidase in the NTS of fructose‐induced hypertensive rats. This study suggests that fructose through GLUT5‐RAGE overexpression induces ROS generation in the NTS, which lead to impairment of AKT‐nNOS‐NO signaling pathway and cause hypertension.Support or Funding InformationMOST104‐2320‐B‐075B‐003‐MY3, 107‐2320‐B‐075B‐002‐MY2This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
DOCA‐salt hypertension and the role of the OVLT‐sympathetic‐gut microbiome axis
Authors: Collister John P. , Nahey David , Hartson Rochelle , Weber Bonnie , Johnson Timothy 
Published: June 2021

Limited studies suggest an association of gut microbiome changes with certain forms of hypertension, but a cause/effect relationship has yet to be fully defined. The deoxycorticosterone acetate (DOCA)‐salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. Indeed, we have recently shown the hypertensive response in DOCA‐treated rats requires the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ that has direct connections to the PVN to increase sympathetic activity. Furthermore, celiac ganglionectomy also supports a role of splanchnic sympathetic innervation to the gut in the hypertensive response to DOCA. Taken together, we hypothesize an OVLT‐sympathetic‐gut (OSG) microbiome axis is involved in the development of hypertension. Having previously reported that the OVLT plays a significant role in the development of DOCA‐salt hypertension, the present study was designed to test the hypothesis that the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. In uninephrectomized OVLT lesioned (OVLTx; n = 5) and SHAM (n = 4) Sprague‐Dawley rats consuming a 2% NaCl diet and 0.9% NaCl drinking solution, 24‐hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). Microbiome analyses were performed on regional gut samples (jejunum, ileum, cecum, and colon) at the end of the study and compared to normal control rats (n=8). The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 157±7 mmHg in SHAM rats by Day 21 of DOCA compared to only 127±5 mmHg in OVLTx rats. Moreover, DOCA hypertension in SHAM rats was associated with decreased levels of Lactobacillus species in the ileum. However, these changes were mitigated and offset by lesion of the OVLT and these bacterial populations in OVLT lesioned rats with attenuated hypertension more closely resembled those in normal control rats. Using Spearman correlation, increasing blood pressure on day 21 correlated with increased Clostridia levels in all tissues, as well as increasing Prevotella and decreasing Bacteroides. We conclude that DOCA‐salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA‐salt in OVLT lesioned rats is mediated in part through counteracting changes in these bacterial populations.Support or Funding InformationSupported by Merial Veterinary Scholars Research Grant and University of Minnesota Grant In AidThis 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 Lipopolysaccharide‐Induced CD11b+ Leukocytes Infiltration in the Kidney: Role of AT2 Receptors
Authors: Patel Sanket Niranjanbhai , Dhande Isha S. , Gray Elizabeth A. , Ali Quaisar , Hussain Tahir 
Published: June 2021

Leukocyte infiltration plays a central role in mediating endotoxemic acute kidney injury (AKI). We have recently shown the anti‐inflammatory and reno‐protective role of angiotensin‐II type‐2 receptor (AT2R) activation under chronic low‐grade inflammatory condition using the obese Zucker rat model. The present study tests the hypothesis that prior activation of AT2R attenuates LPS‐mediated early infiltration of leukocytes, inflammation, and AKI. Mice were pre‐treated with AT2R agonist C21 (0.3 mg/kg), with and without AT2R antagonist PD123319 (5 mg/kg) prior to or concurrently with lipopolysaccharide (LPS, 5 mg/kg) challenge. Pre‐treatment with C21, but not concurrent treatment, significantly prevented the LPS‐induced renal infiltration of CD11b+ leukocytes, increase in the levels of circulating and renal chemotactic cytokines, particularly interleukin‐6 (IL‐6) and markers of renal dysfunction (blood urea nitrogen and albuminuria), while preserving anti‐inflammatory interleukin‐10 (IL‐10) production. Moreover, C21 treatment in the absence of LPS increases renal and circulating IL‐10 levels. To investigate the role of IL‐10 in a cross talk between epithelial cells and monocytes, we performed in vitro conditioned media studies in human kidney proximal tubular epithelial (HK‐2) cells and human monocytes (THP‐1 cells). These studies revealed that the conditioned‐media derived from the C21‐treated HK‐2 cells reduced LPS‐induced THP‐1 TNF‐α production via IL‐10 originating from HK‐2 cells. Our findings suggest that activation of AT2R prior to LPS challenge prevents monocyte infiltration and inflammatory renal injury, possibly via an increase in renal IL‐10 production.Support or Funding InformationThis study was supported by NIH grants R01 DK117495 and R01 DK61578.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exercise Induced Irisin Alleviates Type 1 Diabetic Nephropathy by Promoting Mitochondria Biogenesis and Function
Authors: Majumder Suravi , Pushpakumar Sathnur , Sen Utpal 
Published: June 2021

Mitochondrial dysfunction is known to play an important role in the development and progression of chronic kidney disease. Improving mitochondrial homeostasis therefore has the potential to restore renal function in diabetic kidney disease. Exercise training was shown to be beneficial in improving skeletal muscle and cardiovascular system pathology by improving mitochondrial function, reduction of oxidative stress and metabolic reprogramming. Recent studies have shown that Irisin, a molecule secreted by the skeletal muscles during exercise protects the mitochondria from ischemia reperfusion injury in the lung and heart. In clinical studies, involving type 1 diabetes, high and low levels of Irisin has been reported however, its functional significance remains unclear. Exercise induces the expression of PGC‐1α, leading to the expression of the fibronectin type III domain containing 5 (FNDC5). Irisin derives from the proteolytic cleavage of the peptide FNDC5 by yet unknown enzymes. The purpose of our study was to investigate whether exercise induced Irisin improves mitochondrial biogenesis and function in type 1 diabetic nephropathy. C57BL/6‐Ins2Akita/J (Type 1 diabetes, Akita) and C57BL/6J (Wild type, WT) mice were subjected to 16‐week exercise regimen of 280m run on treadmill at speed of 7m/min for 5 days/week for 2 weeks and increased to 12m/min for the remaining 14 weeks. In vitro experiments were done in mouse glomerular endothelial cells (MGECs) treated with recombinant Irisin. In Akita and WT mice, exercise training improved renal vascularity, cortical blood flow and glomerular filtration rate compared to sedentary groups. Exercise upregulated Irisin expression in Akita and WT mice compared to sedentary mice but to a greater extent in WT mice. The protein and mRNA expression of PGC1α, PPARα and PPARγ were decreased in sedentary Akita mice and increased following exercise training suggesting induction of mitochondrial biogenesis. Sedentary Akita mice showed decreased expression of regulatory markers of mitochondrial DNA transcription, Nrf1, Nrf2, and Tfam and exercise normalized their expression. The expression of MnSOD and catalase were decreased in Akita mice suggesting impaired antioxidant defense and exercise restored their levels to normal. In conclusion, our results suggest that exercise induced Irisin protects the kidney in type 1 diabetes by restoring mitochondrial homeostasis.Support or Funding InformationThis study was supported, in part, by NIH grant HL‐104103 and DK 104653 to US and AHA grant: 15SDG25840013 to SP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protective effects of Dianthus superbus on Diabetic renal dysfunction in in vivo and in vitro models
Authors: Yoon Jung Joo , Son Chan Ok , Kim Hye Yoom , Lee Hyeon Kyoung , Lee Yun Jung , Yang Sun Nye , Lee Ho Sub , Kang Dae Gill 
Published: June 2021

Glomerular fibrosis is caused by accumulation of extracellular matrix proteins in the mesangial interstitial space resulting in fibrosis manifested by either diffuse or nodular changes. Dianthus superbus belongs to the Caryophyllaceae family and has been used in traditional medicine as a diuretic, a contraceptive, and an anti‐inflammatory agent. The aim of this study was to investigate the effects of Dianthus superbus on glomerular fibrosis and renal dysfunction causing diabetic nephropathy in human renal mesangial cells and db/db mice. In diabetic db/db mice models, Dianthus superbus were administrated to db/db mice (n=8) to 10 or 50 mg/kg/day concentrations. The experiment was measured for 8 weeks following Dianthus superbus treatment respectively. As a result, Dianthus superbus significantly ameliorated blood glucose, insulin, HOMA‐IR and HbA1c of diabetic index. Dianthus superbus decreased albumin excretion, creatinine clearance and plasma creatinine. Dianthus superbus ameliorated kidney injury molecules‐1 of kidney function index and C‐reactive protein of inflammation marker. In addition, Dianthus superbus reduced the PAS positivity stain intensity and basement membrane thickening in glomeruli of diabetic nephropathy model. Dianthus superbus suppressed TGF‐β/Smad signaling pathway. Collagen type IV, glomerular fibrosis biomarker, was significantly decreased by Dianthus superbus. Additionally, Dianthus superbus pretreatment attenuated inflammatory factors expression and translocation of nuclear factor kappa B (NF‐κB) in Angiotensin II (Ang II)‐stimulated mesangial cell. These findings suggest that Dianthus superbus has protective effect against renal inflammation, fibrosis and oxidative stress. Therefore, Dianthus superbus may be potential therapies targeting glomerulonephritis and glomerulosclerosis leading to diabetic nephropathy.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High‐Fat Diet Exacerbates Diabetic Kidney Injury in Mice Lacking eNOS
Authors: George Jasmine , Zhao Xueying 
Published: June 2021

Diabetic nephropathy is the leading cause of chronic kidney disease and end stage renal disease. It has been shown that deficiency in endothelial nitric oxide synthase (eNOS), and/or reduced eNOS activity is associated with diabetic nephropathy progression in humans. This study was designed to examine whether high fat diet (HFD) would enhance diabetic kidney injury in eNOS deficient mice. To induce diabetes, six‐week old eNOS deficient mice were placed on normal diet (ND) or HFD (42% from fat). Two weeks later, half of them were rendered diabetic with alloxan. Proteinuria/albuminuria and urinary levels of kidney injury markers were measured in control and diabetic animals 4 months post alloxan injection. There is no difference in urinary total protein among four groups. HFD treatment increased urinary albumin as well as proinflammatory cytokine osteopontin, whereas urinary parameters remained normal in alloxan‐induced diabetic mice fed with normal diet. A combination of HFD and alloxan treatment resulted in a more pronounced albuminuria as well as increased glomerular and tubular damage as evidenced by an elevation of urinary synaptopodin, matrix metalloproteinase‐9 and kidney injury molecule‐1. These results demonstrate that HFD accelerates diabetic kidney injury in eNOS deficient mice. Thus eNOS deficient mice may be suitable for studying the roles of albuminuria and renal lipotoxicity in development and progression of diabetic nephropathy.Support or Funding InformationNIH (SC1DK112151), NIH/NCRR/RCMI (8G12MD007602) and (8U54MD007588)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The protein expression of TNF‐α receptor type 1 (TNFR1) is reduced by nitric oxide (NO) synthase inhibition in cultured renal proximal tubular (HK‐2) cells
Authors: Majid Dewan Syed Abdul , Ekpo Peace Effiong , Talwar Sudha , Abdel‐Mageed Asim B , Castillo Alexander 
Published: June 2021

Tumor necrosis factor‐alpha (TNF‐α) production, stimulated by chronic high salt (HS) intake, has been implicated in salt sensitive hypertension (SSH) though the mechanism is not yet clearly defined. TNF‐α exerts its biological responses via interaction with two cell surface receptors, TNF‐α receptor type 1 (TNFR1) and type 2 (TNFR2). To determine the roles of TNF‐α receptors during the development of SSH induced by NO deficiency, experiments in our laboratory demonstrated earlier that chronic HS intake alone in mice increases TNFR1 protein expression in renal cortical tissues. However, HS intake in mice chronically treated with a non‐specific pharmacological inhibitor of NOS or in knockout mice lacking endothelial NOS decreases TNFR1 protein expression in the renal cortical tissues. We have also demonstrated that chronic angiotensin induced intrarenal angiotensinogen (AGT) generation is augmented in TNFR1 knockout mice, indicating that TNFR1 activity suppressed AGT formation in the kidney. The present study examines the hypothesis that NO linearly regulates TNFR1 activity in the renal tubular cells in a way that NO deficiency decreases TNFR1 expression. The cultured HK‐2 cells (human kidney‐2 cells; HK‐2 (ATCC® CRL‐2190™) are used in these in‐vitro experiments. These cells were plated at a 125,000 cell per density and grown RPMI medium containing 10% FBS and 1% Penstrep, Non‐essential amino acids, Glutamine, Amphotericin B, Gentimicin at 37°c 5% CO2, 99% relative humidity for 24–48h until they reach confluency. Cells were then split into petry‐dishes and treated with drugs Nitro‐L‐arginine methyl ester(L‐NAME) at 0.5 and 1.0 mM concentrations as well as vehicle for 24 hours, harvested, and lysed. Protein concentration was calculated (BCA assay), and the predetermine volume was loaded in each well of the gel (mini‐Protean TGX gel 456–1096). Blot was treated with TNFα receptor 1 (19139 Abcam) antibody and GAPDH. It was observed that TNFR1 expression significantly decreases to 60 ± 25% (n=3) at 0.5 mM and 35 ± 15 % (n=5) at 1.0 mM conc. of L‐NAME treatment, compared to vehicle treatment in HK‐2 cells. The results show that L‐NAME reduces TNFR1 protein expression in HK‐2 cells after treatment for 24 hours in dose dependent manner. As proximal tubular cells are the prime site for intrarenal AGT generation, these data suggest that such decreases in TNFR1 activity induces enhanced AGT production which is involved in the exaggerated hypertensive responses to HS intake in NO deficient condition.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Bilateral renal denervation does not prevent the kidney damage caused by a high fat diet in rats
Authors: Flores‐Sandoval Omar , Cárdenas‐Romero Skarleth , Salgado‐Delgado Roberto , Saderi Nadia 
Published: June 2021

One of the hallmarks of the metabolic syndrome (MS) is the increase of renal sympathetic nerve activity (RSNA), which leads to the upregulation of the renin‐angiotensin system (RAS). Interestingly, the sympathetic hyperactivity in the kidney of obese humans often occurs in absence of overt systemic hypertension. The stimulation of RSNA contributes to the glomerular lesions and the progressive loss of nephron functionality, resulting in acute renal injury (AKI) and, in the long term, chronic kidney disease (CKD), which represent the most common complication of MS. Clinical evidence and animal models of MS have shown that renal sympathetic denervation (RSDN) induces a transient attenuation of the hypertensive symptoms, while the markers of kidney damage continue worsening. Therefore, it is likely that the renal derangement in MS might also depend on the metabolic impairment, such as the upregulation of plasma leptin and insulin, independently from the RSNA. To investigate this issue, we explored the effect of MS over blood pressure and kidney functionality, in intact and renal denervated rats. For that, animals were either fed with a standard diet (SD) or a high‐fat diet for 12 weeks (HFD), with or without bilateral renal denervation performed at the beginning of protocol (n = 6). Results indicate that, as expected, HFD in intact animals promotes fat accumulation, glucose intolerance and hypertension, but also decreases water consumption and induces marked proteinuria from week 7, slight hematuria from week 9, with respect to SD rats. Remarkably, the renal denervation prevents the changes that HFD triggered in blood pressure and renal parameters only in the short and medium term, but it is ineffective in the long term. On the bases of these results, we suggest that the hypertension associated to MS is not only due to hyperactivation of RSNA, but it could involve hormonal/hemodynamic factors, typical of metabolic impairment, which could contribute to renal injury.Support or Funding InformationCONACYT‐CB‐243298This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.