bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrolyte Homeostasis in Migraine
Authors: Stanton Angela A 
Published: November 2023

Migraine is considered to be a neurovascular disease. Most research is aimed at reducing migraine pain by medications that either limit the activity of an overstimulated brain or add neurotransmitters that are presumed to be below ideal levels in a migraine brain (1, 2). In this presentation, a new view is discussed. Taking a closer look at metabolic deficits in migraineurs (3–9), we can see that it is their metabolic processes that disrupt electrolyte homeostasis prior to migraine. Some of these metabolic deficiencies are genetic and others are caused by medicines. The reestablishing of electrolyte homeostasis can prevent migraine. Migraineurs have special sensory sensitivities with sensory neurons that have more receptor connections than regular brains (10). Neurons that are more sensitized and have more receptor connections require higher ionic concentration electrolytes to keep their overactive work function. The lack of proper electrolyte is likely the cause of cortical depression and the ensuing cortical spreading depression—the wave that reaches the pain sensors in the meninges. A solution is offered for preventing pain without medical intervention by reducing electrolyte disrupting elements in the diet of migraineurs to the minimum required, such as glucose, and ensuring a constant proper electrolyte balance by a potassium and magnesium heavy diet with more sodium than what the average population uses. In the past three years of my observation of migraineurs in the Facebook group I specifically designed for reaching electrolyte homeostasis, all migraineurs can stop their medicines and remain migraine free—provided they maintain this balance.Support or Funding Informationno funding receivedno conflict of interest
Food restriction increases the cardiovascular response evoked by angiotensin‐[1–10] and angiotensin‐[1–7] in female Fischer rats
Authors: de Souza Aline Maria Arlindo , Pai Amrita , Ji Hong , Menezes Rodrigo , Sandberg Kathryn 
Published: November 2023

Anorexia is associated with cardiovascular dysfunction including hypotension and cardiac arrhythmias. In a rat model of food restriction (FR) we previously demonstrated that the activity of endothelial α1 adrenergic receptors and brain type 1 angiotensin receptors were increased. The aim of this study was to determine the role of the angiotensin (Ang)‐[1–7] and Ang‐[I‐10] in the brain. Female Fischer rats (220g, 4 mo) were maintained for 14 days on a FR diet, that was 40% of the control group (C) food intake. Cannulas were implanted in the lateral ventricle (LV) on day 7. On day 14, the animals were catheterized with a polyethylene tube in the femoral artery for recording of mean arterial pressure (MAP) and heart rate (HR). After 14 days, MAP (mmHg) [C: 105±1, n=35 vs. FR: 102±2, n=36; p<0.05] and HR (bpm) [C: 386±5, n=35 vs. FR: 353±8, n=36, p<0.001] were reduced in the FR. Injection of Ang‐[1–7] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group (25pmol) [C: Δ −2±1, n=8 vs. FR: Δ 7±1, n=10; p<0.05]. Moreover, there was a greater increase in HR (Δ bpm) in the FR compared to the C group [C: Δ 9±3, n=8 vs FR: Δ 29±9, n=10; p<0.05]. Injection of Ang‐[1–10] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group (25pmol) [C: 5±1, n=7 vs. FR: 13±2, n=7; p<0.005]; however, there was no effect on HR. This Ang‐[1–10]‐induced increase in MAP was attenuated by administering captopril into the LV, in both the FR and C groups, suggesting this increase in MAP was mediated by angiotensin converting enzyme. These results suggest that increased Ang‐[1–7] and Ang‐[1–10] activity in the brain play a role in the increased sympathetic activity observed in anorexia.Support or Funding InformationNIH 1R01HL119380 (KS)UFOP (AS)CAPES (AS)
The Effect of Renal pH on Ischemia‐Reperfusion‐Induced Acute Kidney Injury
Authors: Boone Jasmine E , Ruisheng Liu 
Published: November 2023

Acute kidney injury (AKI) is a major public health issue associated with significant cost, extensive morbidity and increased mortality. However, no specific therapy to prevent or treat AKI is available, and the pathophysiological mechanisms of AKI remain unclear. Renal pH is related to dietary acid‐base load and affects the function of epithelial cells. Renal alkali intervention has been demonstrated to improve renal function and slow the decline in glomerular filtration rate (GFR) in the normal population and patients with chronic kidney disease. However, the role of renal pH in AKI is still not known.In the present study, we hypothesized that elevations in renal pH protect against the development of ischemia reperfusion injury (IRI)‐induced AKI. AKI was induced in C57BL/6J mice by 18 minutes of ischemia bilateral clamping of renal pedicles. The mice that were performed same surgery without clamping pedicels were taken as sham group. The mice were then divided into three groups (n=6 per group) treated for 14 days with 0.5% NaCl, 0.72% NaHCO3 (same mEq of Na+ as in NaCl), or 0.46% NH4Cl (same mEq of Cl− as in NaCl).Urine pH was significantly increased to 7.8±0.5 in the NaHCO3 treated group and decreased to 6.8±0.3 in the NH4Cl treated group, compared with the NaCl group (7.3±0.3). Plasma creatinine was measured 7 and 14 days after IRI to evaluate renal injury. The plasma creatinine was substantially increased in all three groups compared with the sham‐operated group (0.08±0.02 mg/dl) 7 days after IRI, with the NH4Cl group being the highest (0.98±0.15 mg/dl), followed by the NaCl group (0.71±0.11 mg/dl) and the NaHCO3 group (0.47±0.09 mg/dl). There was no significant difference in plasma creatinine between the three groups at 14 days after IR. To evaluate kidney function, GFR was measured by the clearance of plasma FITC‐insulin with a single bolus injection in conscious mice at baseline as well as 7 and 14 days after IRI. GFR decreased by 44.5% (244.7±9.1 to 135.8±13 μl/min) in the NH4Cl group, 31.8% (228.3±11 to 155.52±8.4 μl/min) in the NaCl group and 21.2% (237.6±7.5 to 187.3±14 μl/min) in the NaHCO3 group 7 days after IRI. The GFR returned to near baseline in all three groups at 14 days after IRI.In summary, these results indicate that renal acidification aggravates whereas alkalization protects against the development of IR‐induced AKI.
Dietary oxalate induces monocyte mitochondrial dysfunction and crystalluria in healthy subjects: A role of spinach in kidney stone disease?
Authors: Mitchell Tanecia , Yarlagadda Vidush , Patel Mikita , Knight John , Assimos Dean , Holmes Ross 
Published: November 2023

Dietary oxalate contributes significantly to urinary oxalate excretion and is linked to calcium oxalate kidney stone formation. Oxalate is a common component found in kidney stones and in plants such as spinach. We have previously shown that patients with calcium oxalate kidney stone disease have decreased mitochondrial function and increased IL‐6 levels compared to healthy subjects. The purpose of this study was to investigate whether a dietary oxalate load has any effect on monocyte mitochondrial function and urinary oxalate levels in healthy subjects. Nine healthy subjects between the ages of 21 and 31 with an average BMI of 24.6 ±1.2 were included in the study. Participants consumed a low oxalate diet for 3 days prior to drinking a high dietary oxalate load (spinach smoothie). Blood and urine was collected from participants prior to consuming a high oxalate spinach load (pre‐smoothie) and 5 hours following smoothie consumption (post‐smoothie). Monocyte mitochondrial function was measured using Seahorse XF96 technology. Urinary oxalate levels (both crystalline and soluble) were determined using ion chromatography‐mass spectrometry. The high dietary oxalate load caused a significant decrease in monocyte mitochondrial function in healthy subjects. These responses were similar to levels previously found in patients with calcium oxalate kidney stone disease. In addition, both crystalline and soluble urinary oxalate levels were significantly increased in post‐smoothie samples compared to pre‐smoothie samples. These findings suggest that a high dietary oxalate could affect monocyte mitochondrial function in patients. Future studies will investigate potential mechanisms responsible for these findings.Support or Funding InformationThis work was supported by NIH K01DK106284 and the UAB Department of Urology.
Knockout of Sphingosine Kinase 1 Attenuates Renal Interstitial Fibrosis in Unilateral Ureteral Obstruction (UUO) Model
Authors: Zhang Xiwen , Wang Fan , Wang Weili , Li Pin‐Lan , Comlekoglu Tien , Li Ningjun 
Published: November 2023

Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite and an important signaling molecule that plays a significant role in the differentiation of fibroblasts to myofibroblasts. S1P synthesis is catalyzed by sphingosine kinases (SPHK), which phosphorylate sphingosine into S1P. The present study tested the hypothesis that Sphk1‐S1P signaling pathway participates in the kidney damage in unilateral ureteral obstruction (UUO) model using Sphk1 knockout mice. UUO was created by ligation of the ureter on one kidney and the contralateral kidney is used as control. Wild type C57BL6 mice and Sphk1 KO mice were subjected to UUO for 14 days and four groups of kidneys were collected: wild type control group (WT‐C), wild type UUO group (WT‐UUO), knockout control group (KO‐C) and knockout UUO group (KO‐UUO). The mRNA level of Sphk1 in WT‐UUO was increased by 4 fold (p<0.05 vs. WT‐C) and there was no significant difference between other three groups. The protein levels of α‐smooth muscle actin (α‐SMA) and collagen I were upregulated in both UUO groups but the levels were significant lower in KO‐UUO group than in WT‐UUO group. The relative protein levels of α‐SMA were 1 ± 0.03 in WT‐C, 18.13 ± 2.55 WT‐UUO, 1.95 ± 0.67 KO‐C, and 9.54 ± 3.55 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO; collagen I levels were 1 ± 0.13 in WT‐C, 11.25 ± 1.74 WT‐UUO, 0.93 ± 0.58 KO‐C, and 3.09 ± 1.15 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO. Immunostaining showed that the percentage of lymphocyte marker CD43 positive cells was much higher in both UUO groups than in two control groups, but there was no significant difference between KO‐UUO and WT‐UUO, suggesting that the differences of renal fibrotic markers between WT‐UUO and KO‐UUO are not due to the change of immune regulation by knockout of Sphk1, rather, it is the direct effect of Sphk1 knockout on renal cells. Finally, the tubular injury score and glomerulosclerosis index were significantly lower in KO‐UUO than in WT‐UUO in kidney tissue slides with PAS staining (Tubular injury score: 0.07 ± 0.01 in WT‐C, 2.66 ± 0.17 WT‐UUO, 0.03 ± 0.02 KO‐C, and 1.21 ± 0.16 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO; Glomerulosclerosis index: 0.62 ± 0.12 in WT‐C, 2.24 ± 0.14 WT‐UUO, 0.43 ± 0.05 KO‐C, and 1.50 ± 0.10 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO). These results suggest that Sphk1‐S1P signaling pathway mediates kidney damage in UUO mice. Manipulating Sphk1‐S1P signaling pathway may be used as a therapeutic strategy in renal interstitial fibrosis.Support or Funding InformationSupport: NIH grant HL89563
Administration of Tempol Improves Renal Autoregulation in Ischemia‐reperfusion Induced Acute Kidney Injury
Authors: Guan Zhengrong , Ryoo Chan Woo , Inscho Edward W 
Published: November 2023

Renal autoregulation is critical for protecting the kidney from fluctuations in arterial pressure by regulating renal vascular resistance to maintain stable renal perfusion and glomerular filtration rate (GFR). Renal ischemia‐reperfusion (IR) induced acute kidney injury (IR‐AKI) is characterized by reduced renal blood flow and a decline in GFR. We hypothesized that increased reactive oxygen species (ROS) contribute to impairment of renal autoregulatory capability in IR‐AKI. Afferent arteriole autoregulatory behavior was assessed using the in vitro blood‐perfused juxtamedullary nephron preparation. IR‐AKI was induced by 60 minutes of bilateral renal artery occlusion followed by 24 hours of reperfusion. We found that plasma creatinine was increased in IR rats (3.86 ± 0.2 mg/dl) compared to 0.93 ± 0.07 mg/dl in sham rats (n=6–7, p<0.05). Baseline afferent arteriole diameter averaged 13.0 ± 0.4 μm (n=5) in kidneys from sham rats and these arterioles exhibited normal autoregulatory behavior. Decreasing renal perfusion pressure from 100 to 65 mmHg increased arteriole diameter from 13.0 ± 0.4 to 15.1 ± 0.8 μm, corresponding to 116 ± 5% of the baseline diameter. Subsequent stepwise increases in perfusion pressure (15 mmHg) caused pressure‐dependent afferent arteriole vasoconstriction to 66 ± 2% of baseline diameter at 170 mmHg. In contrast, pressure‐mediated afferent arteriole responses were markedly attenuated in IR‐AKI rats. Baseline diameter averaged 11.7 ± 0.6 μm and remained between 91 and 101% of baseline over the 65–170 mmHg pressure range tested, indicating a loss of autoregulatory function. In another set of IR‐AKI rats, acute administration of the ROS scavenger, tempol (10−3 M), to afferent arterioles increased baseline diameter by 10 ± 2% from 11.3 ± 0.8 to 12.2 ± 0.9 μm (n=5). Furthermore, scavenging ROS production improved autoregulatory behavior of afferent arterioles from IR‐AKI rats. During exposure to tempol, decreasing renal perfusion pressure from 100 to 65 mmHg resulted in a diameter increase to 110 ± 2 % of the control diameter while increasing perfusion pressure to 170 mmHg decreased arteriole diameter to 78 ± 1% of control (P<0.05 vs IR). In conclusion, these results suggest that renal ischemia‐reperfusion leads to impaired autoregulatory behavior of afferent arterioles. Acutely scavenging endogenous ROS with tempol improves afferent arteriole autoregulatory responsiveness, suggesting that excessive ROS production contributes to impaired renal autoregulation in IR‐AKI.Support or Funding InformationThis study is supported by a Grant‐in‐Aid (15GRNT25240015) from the American Heart Association for ZG and by grants from NIH (DK044628, HL074167, HL098135 and HL095499) for EWI.
Role of carbonic anhydrase in acute recovery following renal ischemia reperfusion injury
Authors: Nensén Oskar , Hansell Peter , Palm Fredrik 
Published: November 2023

Ischemia reperfusion injury is a common cause of acute kidney injury in the clinic. It has previously been reported that kidney oxygen consumption (QO2) in relation to glomerular filtration rate (GFR), and thus sodium load, is markedly increased following an ischemic insult. Since proximal tubular sodium transport (TNa) is a major contributor to overall QO2, we investigated how inhibition of TNa in this particular tubular segment impacted on oxygen metabolism and kidney function during the acute recovery following 45 minutes of warm ischemia by inhibiting carbonic anhydrase using acetazolamide.Male Sprague Dawley rats were anesthetized and administered acetazolamide (50 mg/kg; n=11) or volume‐matched vehicle (n=12). Kidney function, hemodynamics and QO2 were determined before and after complete ischemia by clamping the renal artery.Acetazolamide per se reduced GFR (−20%) and TNa (−22%), while it increased urine flow (+91%) and urinary sodium excretion (+3600%). Renal blood flow was reduced (−31%) as a result of increased renal vascular resistance (+37%) but without affecting QO2.Ischemia reperfusion per se resulted in similar decrease in GFR, TNa, and TNa/QO2 independently of carbonic anhydrase status. However, the QO2/GFR ratio following ischemia‐ reperfusion was profoundly increased in the group receiving carbonic anhydrase inhibition indicating a significant contribution of basal oxygen metabolism to the total kidney QO2 following inhibition of proximal tubular function after an ischemic insult.Support or Funding InformationSwedish Research Council ‐ Medicine and Health
C5aR2 Deficiency Improves Renal Regeneration after Renal Ischemia Reperfusion Injury and in Kidney Transplantation in Mice
Authors: Thorenz Anja , Chen Rongjun , Rong Song , Klemann Christian , Haller Hermann , Braesen Jan Hinrich , Klos Andreas , Gueler Faikah 
Published: November 2023

ObjectiveThe complement receptors C5aR1 and C5aR2 serve distinct roles in immune regulation. In kidney transplantation ischemia reperfusion injury (IRI) results in rapid complement activation. In this study C5aR1 and C5aR2 deficient mice were tested in a model of renal ischemia reperfusion injury (IRI) and in an isogenic cross over kidney transplantation (ktx) model.MethodsIRI was induced by unilateral clipping of renal pedicle for 45 min in C5aR1, C5aR2 −/− and wild type mice (WT). Renal morphology, inflammation, peritubular capillary density and renal fibrosis were investigated by immunohistochemistry. FACS analysis was done at d7 after IRI to analyze infiltrating subsets of myeloid and lymphocytes. To study renal perfusion impairment due to IRI arterial spin labelling was done. In a second model isogenic ktx with prolonged cold ischemia time of 90 min was performed and C5aR1−/−, C5aR2−/− or WT mice served as donors or recipients.ResultsWT mice showed dramatic decrease of renal perfusion and severe inflammation resulting in interstitial fibrosis at three weeks after IRI with substantial loss of kidney volume. C5aR2 −/− mice had less inflammation and started to regenerate at 7 days after IRI. Renal fibrosis was attenuated in C5aR2−/− mice which had less rarefication of peritubular capillaries compared to WT IRI kidneys. In the ktx model C5aR2 −/− of the recipient showed the best renal morphology with attenuated renal ischemia reperfusion injury of the graft. By FACS analysis differential activation in γδ‐Tcells in C5aR2 deficient mice was observed and may have contributed to enhanced regeneration.ConclusionC5aR2 deficiency attenuates renal damage and fibrosis in renal IRI and ktx by better regeneration and protection of capillary integrity of the renal tissue.
Gut Microbial Metabolite Trimethylamine‐N‐Oxide Instigates NLRP3 Inflammasomes Activation and Podocyte Injury
Authors: Koka Saisudha , Zhang Yang , Li Ningjun , Hussain Tahir , Li Pin‐Lan , Boini Krishna M 
Published: November 2023

Gut microbe derived metabolite, Trimethylamine‐N‐oxide (TMAO) is elevated in chronic kidney disease (CKD) and contributes to the progression of renal disease and increases the risk of mortality in CKD. However, it remains unknown how TMAO induces chronic kidney diseases. The present study tested whether TMAO induces NLRP3 Inflammasomes formation and activation and thereby contributes to podocyte injury. Confocal microscopic analysis showed that TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase‐1 in podocytes compared to control cells. Pretreatment with Nlrp3 siRNA or Caspase‐1 inhibitor YVAD abolished the TMAO‐induced NLRP3 inflammasome formation. Correspondingly, TMAO treatment significantly increased the caspase‐1 activity (2.5 fold) and IL‐1β production (2.4 fold) compared to control cells. The Nlrp3 siRNA transfection significantly attenuated the TMAO‐induced caspase‐1 activity and IL‐1β production. Further RT‐PCR and confocal microscopic analysis showed that TMAO treatment significantly decreased the podocin expression (podocyte damage) compared to control cells. However, pretreatment with Nlrp3 siRNA or YVAD attenuated the TMAO‐induced podocin reduction. Furthermore, Nlrp3 siRNA transfection was found to preserve podocyte morphology by maintaining the distinct arrangement of F‐actin fibers normally lost in response to TMAO. It also prevented podocyte dysfunction by restoring TMAO‐induced suppression of VEGF production and secretion. Based on these results, it is concluded that TMAO‐induced the NLRP3 inflammasome formation and activation in podocytes and thereby by resulting in podocyte injury.Support or Funding InformationDK104031
Development of kidney‐specific resources for analysis and visualization of genomic data
Authors: Gonzalez‐Vicente Agustin , Hopfer Ulrich , Garvin Jeffrey L 
Published: November 2023

The usefulness of modern genomic techniques which produce vast amounts of data is largely limited by our ability to analyze and interpret it. To manage big data, several digital platforms have been developed that use signaling and metabolic pathways to help with analysis and visualization. However, most of these pathways are based on human data, lack tissue/cell specificity and don't distinguish between isozymes. This makes it difficult to employ them to analyze genomic data from model systems. Thus, most available pathways are inadequate for kidney research. To fill this gap, we have been developing nephron segment‐specific pathways on the public depository Wikipathways using Rattus novergicus as a model organism. Wikipathways is an open platform, making it easy for anyone to edit and improve the pathways. Files in Wikipathways are also freely available to download and customize for publication. Before our contributions, there were only three pathways available directly related to renal physiology: Renin Angiotensin System (PW376), Vasopressin and Aquaporins (WP2662), and Glomerulosclerosis (WP2572). Thus far we have incorporated five new pathways. Two of these pathways list segment‐specific transporters from proximal tubules (WP3881) and thick ascending limbs (WP3882). The others summarize the enzymes involved in: 1) fructose and glucose metabolism in proximal tubules (WP3894); 2) lipid metabolism in proximal tubules (WP3901) and; 3) signaling cascades by which angiotensin II acutely affects transport in thick ascending limbs (WP3887). To create these pathways we drew data from multiple publications and databases. The enzymes, represented as nodes, are annotated using ENTREZ Gene ID. Annotations provide links to external databases for further research, and serve as an identifier for each node to merge the pathway with experimental data. In summary, the pathways we developed fill a specific need for the renal research community. Crowd contributions by renal physiologist to further develop these pathways and to create similar ones would provide a powerful and freely‐available tool for renal genomic research.Support or Funding InformationThis work was supported in part by a grant from the Heart, Lung and Blood Institute of the National Institutes of Health to J. L.G. (HL128053).