bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Expression of the (Pro)renin Receptor in the Subfornical Organ of Hypertensive Humans
Authors: Cooper Silvana G , Yamamoto Rieko , Jensen Dane D , Sorensen Jacob T , Trivedi Darshan , Xiong Zhenggang , Feng Yumei 
Published: November 2023

We previous reported that (pro)renin receptor (PRR) is functional important in the subfornical organ (SFO) of the brain, a key brain circumventricular organ that is involved in BP regulation and body fluid homeostasis. The SFO PRR mediates Ang II formation and is critical for hypertension development and body fluid homeostasis in hypertension animal models. However, it is not known whether PRR expression level is altered in hypertensive humans and what is the cellular distribution. We have collected human subfornical organ (SFO) tissues post mortem, of which 14 are clinically diagnosed hypertensive and 7 are diagnosed normotensive. Systolic (SBP) and diastolic (DBP) blood pressure, age, body weight, and medications used information was collected. SFO tissues were fixed in 10% formaldehyde and processed for paraffin embedding and sectioning. The age and body weight patterns are similar between the normotensive and hypertensive subjects. Regardless of anti‐hypertension medications, the SBP was significantly higher in clinical diagnosed hypertensive (142.4 ± 4.2 mmHg) compared with the normotensive (118.1 ± 7.7, P=0.007) subjects. There is no difference in DBP between these two groups (74.1±5. VS. 79.29±3.5). SFO sections were used for immunofluorescence double labeling of human PRR with neuronal marker (anti–human neuronal protein HuC/HuD), astrocyte marker (glial fibrillary acidic protein, GFAP), or microglia marker (ionized calcium‐ binding adaptor molecule 1, Iba1). We found that the human PRR is co‐localized only with the HuC/HuD but not GFAP or Iba1 suggests that PRR is majorly expressed in the neurons of human SFO. To examine whether there is alteration of PRR expression in the hypertensive humans, we performed immunohistochemistry labeling of PRR in these tissues. The PRR immuno‐reactivity was significantly higher in the hypertensive subjects (145.3 ± 1.4 Arbitrary Units, AU) compared with the normotensive subjects (135.5 ±1.2 AU, P=0.0002). In addition, there is significant positive correlation between the PRR expression levels and the SBP (Pearson r=0.55, R2=0.308, P=0.018) among all normotensive and hypertensive subjects. The data suggests that PRR expression level is elevated in hypertension subjects and there is positive correlation of PRR expression level with systolic BP. We conclude that PRR in the SFO may play important role in the body fluid homeostasis and hypertension development in humans.Support or Funding InformationNIH/NHLBI (1R01HL122770) TO YUMEI FENG; NIH/NIGMS (P20GM103440) TO SILVANA G. COOPER
Meprin β expression enhances multi bacterial sepsis‐induced acute kidney injury
Authors: Yahaya Ismaila , Niyitegeka Jean‐Marie Vianney , Fernander Mizpha Courtney Simone , Sedighi Rashin , Kenley Sharniece R , Ahmed Faihaa , Boston Ava Millicent , Ongeri Elimelda Moige 
Published: November 2023

Sepsis is a systematic inflammatory response syndrome which accounts for 51% of reported cases of acute kidney injuries (AKI) in intensive care units (ICU) and is associated with high morbidity and mortality. The high mortality rate associated with AKI is partly due to the fact that underlying mechanisms are not fully understood. Meprins are metalloproteinases of the astacin family which are most highly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages). Meprins have been shown to play a role in the pathophysiology of acute kidney injury and in leukocyte infiltration. This study was designed to determine how meprin expression impacts the pathology of AKI induced by sepsis. To this end, cecal ligation and puncture (CLP) was used to induce multi‐bacterial sepsis in 12‐week old wild‐type (WT) and meprin β knockout (βKO) mice on a C57BL/6 background. The mice were sacrificed at 18 h post‐CLP. Blood samples were collected by tail nicking at 0 h and by cardiac puncture at 18 h post‐CLP. For biochemical assessment of kidney injury, enzyme linked immunosorbent assays were used to measure plasma neutrophil gelatinase‐associated lipocalin (NGAL) and cystatin C levels. The 18 h post‐CLP survival rates were comparable for WT and meprin βKO mice. The levels of cystatin C at 18 h post‐CLP were significantly higher in both genotypes for mice subjected to CLP when compared to sham operated controls (p≤0.0001). More importantly, WT mice subjected to CLP had significantly higher levels of plasma cystatin C when compared to the meprin βKO counterparts. Furthermore, there was a significant increase in NGAL levels in WT mice subjected to CLP but not in meprin βKO counterparts (p≤0.05). The results indicate that meprin β plays a detrimental role in sepsis‐induced acute kidney injury. The data further suggests that when compared to NGAL, cystatin C is a better biomarker for kidney injury induced by sepsis.Support or Funding InformationThis study was supported by the National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) under Award # SC3GM102049 to Elimelda Moige Ongeri.
SCUBE1‐enhanced Bone Morphogenetic Protein Signaling Protects against Acute Kidney Injury
Authors: Liao Wei‐Ju , Lin Heng , Cheng Ching‐Feng , Yang Sung‐Sen , Chen Ann , Yang Ruey‐Bing 
Published: November 2023

Acute renal failure represents a common clinical problem associated with high morbidity and mortality. Renal ischemia‐reperfusion (I/R) is the major cause of acute renal failure in the native and transplanted kidneys. It has been reported that bone morphogenetic protein 7 (BMP7) reduces severity of injury via its proliferative and anti‐apoptotic effects on tubular cells after renal I/R insult. Our previous study showed that a novel secreted and membrane‐tethered protein SCUBE1 (signal peptide‐CUB‐EGF domain‐containing protein 1) was up‐regulated in renal tubular epithelium and may be involved in renal regeneration and repair after I/R injury (Nephrol. Dial. Transplan. 25: 1421, 2010). However, the precise mechanism underlying its protective function after renal I/R insult remains largely unknown. To further elucidate the renal pathophysiological roles of SCUBE1, we generated new Scube1 deletion (Δ2) mouse. As compared with wild‐type littermates, Δ2 mice showed severe renal histopathologies (extensive loss of brush border, tubular necrosis, and tubular dilation) and increased inflammation (neutrophil infiltrate and induction of tumor necrosis factor α) during the resolution of I/R damage. They also showed elevated levels of biomarkers of acute renal injury (neutrophil gelatinase‐associated lipocalin and kidney injury molecule‐1), and reduced BMP signaling (phosphorylated Smad1/5/8) along with decreased proliferation and increased apoptosis in renal tubular cells. Moreover, molecular and biochemical analyses revealed that SCUBE1 directly binds BMP7 and its receptors, possibly functioning as a BMP co‐receptor to promote BMP7 signaling. Importantly, lentivirus‐mediated overexpression of SCUBE1 enhanced BMP signaling and conferred a concomitant survival outcome for Δ2 proximal tubular epithelial cells after hypoxia–reoxygenation treatment. The protective BMP7 signaling may be facilitated by stress‐ inducible SCUBE1 after renal I/R, which suggests potential targeted approaches for acute kidney injury.Support or Funding InformationThis work was supported by Ministry of Science and Technology Grants of Taiwan [grant number NSC 102‐2320‐B‐001‐015‐MY3 (to R.‐B. Y.)]
Rifaximin Effects on Serum Trimethylamine‐n‐oxide in Chronic Kidney Disease
Authors: Johnson Cassi , Zhang Shiqin , Omede Faith , Stubbs Jason 
Published: November 2023

IntroductionTrimethylamine‐n‐oxide (TMAO) is a byproduct of intestinal bacteria metabolism of choline and L‐carnitine. In patients with chronic kidney disease (CKD), TMAO accumulates in the bloodstream and is thought to perpetuate kidney fibrosis and promote cardiovascular disease (CVD). We hypothesized that rifaximin, a broad‐spectrum oral antibiotic with poor bioavailability, would significantly lower serum TMAO levels and slow kidney disease progression in CKD mice.DesignCKD mice were generated by feeding C57BL/6J mice a diet containing 0.2% adenine; non‐CKD mice received the same diet without adenine supplementation. To test whether acute rifaximin therapy could lower serum TMAO levels, mice were fed the 0.2% adenine or control diet for 7 weeks. Starting at week 6 of the study, mice were randomized to receive 50 mg/kg rifaximin or vehicle once daily for the final week. In a separate study to assess whether long‐term rifaximin therapy could lower serum TMAO levels and attenuate kidney disease, 50 mg/kg rifaximin or vehicle therapy was administered 5 days/week (M‐F) at the onset of CKD induction by 0.2% adenine diet and continued for 13 weeks.ResultsAcute rifaximin therapy lowered post‐treatment serum TMAO levels in both non‐CKD (0.76 ±0.41 μM for rifaximin vs 3.78±1.45 μM for vehicle; p=NS) and CKD mice (8.91±2.20 μM for rifaximin vs 15.92±1.67 μM for vehicle; p<0.01). We observed shifts in microbiome composition with rifaximin therapy reflected by a decrease in microbiome diversity when comparing stool samples collected pre‐ and post‐rifaximin treatment that could account for decreased serum TMAO (Shannon H test: 2.51±0.01 for rifaximin vs 3.42±0.15 for vehicle in non‐CKD mice; 2.37±0.09 for rifaximin vs 3.53±0.25 for vehicle in CKD mice). However, long‐term rifaximin therapy did not lower serum TMAO levels in non‐CKD (6.87±1.13 uM for rifaximin vs 10.21±1.58 for vehicle; p=NS) or CKD mice (41.08±5.78 for rifaximin vs 45.51±3.89 for vehicle; p=NS). Likewise, rifaximin therapy failed to alter CKD progression as assessed by both serum markers of renal function and gene markers of kidney fibrosis.ConclusionOur data suggests that rifaximin therapy may be a viable option for short‐term lowering of serum TMAO in CKD; however, long‐term administration of this drug does not sustain this TMAO‐lowering effect or alter CKD progression in mice.
Urine Osmolality as a Diagnostic Tool for High Risk for Kidney Stone Development in Patients with Recurrent Kidney Stones
Authors: Suh Hyun‐Gyu , Kavouras Stavros A , Gharbi Kakam , Mauromoustakos Andy A , Vallet Marion , Tack Ivan 
Published: November 2023

Formation of kidney stone affects approximately 1 in 11 people in the U.S., and it can develop into various adverse renal outcomes. Although American Urological Association guideline recommends having at least 2.5 L of urine daily by having a high fluid intake to reduce 50% of recurrence rate in stone formers, few studies have evaluated the association between urine concentration as a marker of hydration status and the risk of kidney stone formation.PURPOSETo identify the threshold of optimal hydration in order to classify patients as high risk for kidney stone formation.METHODSTotal of 302 subjects from Southern France with a history of recurrent kidney stones were retrospectively included in the study (female: 40.4 %, age: 46±14 y, BMI: 25.3±5.0 kg·m−2). Tiselius calcium oxalate crystallization risk index (CRI) was calculated based on urinary calcium (6.42±3.60 mmol·24h−1), oxalate (0.36±0.14 mmol·24h−1), citrate (32.0±17.5 mmol·24h−1), and magnesium (4.31±1.74 mmol·24h−1) from 24 h samples. The ability of 24 h urine osmolality to classify patients as high risk for kidney stone crystallization was examined through the receiver operating characteristic (ROC) curve analysis. High risk for kidney stones crystallization was defined as CRI >1.61 and >1.18, for males and females, respectively. The correlation coefficient was also examined between 24 h urine osmolality (538±198 mOsm·kg−1) and 24 h urine volume (1,948±823 mL·24h−1) and 24 h CRI (1.23±0.71).RESULTSThe overall accuracy for diagnosing high risk of stone formation (AUC, area under the curve) was 84.9%, with threshold of 577 mmol·kg−1 (sensitivity: 78.4%, specificity: 81.6%) for the entire sample. When data where analyzed by gender, AUC for females was 84.6%, with cut‐off point of 501 mmol·kg−1 (sensitivity: 83.3%, specificity: 76.0%). Males had AUC of 85.8% with thresholf of 577 mmol·kg−1 (sensitivity: 85.5%, specificity: 77.6%). A moderate negative association was found between urine volume and urine osmolality (r=−0.632, P<0.05). Also a moderate but positive association was found between 24 h urine osmolality and Tiselius CRI index (r=0.638, P<0.05).CONCLUSIONUrine osmolality >501 and >577 mmol·kg−1 was assosicated with greater risk for kidney stone formation in patiens with history of recurrent kidney stone.
DPP4 Gene Deletion Protects Mice from Larp6‐mediated Fibrosis in Progressive Kidney Injury Models
Authors: Nistala Ravi , An Jianzhong , Kandikattu Hemanth Kumar , Bysani Chandrasekar 
Published: November 2023

Obesity and heightened activity of the renin‐angiotensin‐aldosterone system (RAAS) are known risk factors for kidney injury and proteinuria. Progression of kidney injury occurs due to increase in inflammation, tubulointerstitial fibrosis and loss of nephron mass. Dipeptidyl peptidase 4 (DPP4) inhibition has been shown to improve proteinuria in both humans with Type 2 diabetes (SAVOR‐TIMI) and rodent models of obesity and diabetes. We and others have previously reported that DPP4 may be upregulated with increased activity in diabetic humans and rodent models of obesity and diabetes. DPP4 is known to bind collagens and fibronectin. Larp6 is a profibrotic gene that upregulates collagen synthesis via binding to the 5′ stem‐loop (5'SL) region of collagen mRNA. Therefore, we hypothesized that DPP4 gene deletion will prevent Larp6‐mediated fibrosis in a model of progressive kidney disease. To test our hypothesis, we fed a cohort of mice (DPP4+/+ and DPP4−/−) for 6 months on a Western diet (46% Kcal fat, 34% Kcal refined sugars) and a second cohort with angiotensin II (Ang II; 1000ng/kg/min via osmotic pump) plus deoxycorticosterone (DOCA, 50mg pellet) plus 0.9% salt for 2 weeks. We observed a significant increase in proteinuria in DPP4+/+ mice in both treatment groups, while a reduction in creatinine clearance (CrCl) was observed in the Western diet‐fed mice only. Pro‐inflammatory IL‐2 and IFN‐γ secretion was increased in kidney CD4+ T cells, while anti‐inflammatory IL‐10 secretion was decreased in the obese mice. This was accompanied by an increase in kidney fibrosis as assessed by picrosirius red staining and Collagen III/fibronectin expression as assessed by immunoblots. Importantly, an increase in kidney Larp6 protein was observed in both the obese and the RAAS activation models. DPP4 gene deletion abrogated the increases in proteinuria and the decrease in CrCl concurrently with increases in kidney inflammation and fibrosis. Furthermore, Larp6 protein levels were significantly lowered in the DPP4 knockout mice. These findings suggest that in conditions of progressive kidney injury, both DPP4 and Larp6 are activated. Moreover, DPP4 may regulate Larp6 expression and kidney fibrosis, thereby identifying DPP4 inhibition as a viable strategy to mitigate progressive kidney injury leading to end stage kidney disease and dialysis.Support or Funding InformationRavi Nistala was supported by research grant from Dialysis Clinics Inc., MU Research Board and Department of Medicine Research Council. Chandrasekar Bysani was supported by a VA Career Research Scientist Award
Aerobic exercise training prevents renal damage in insulin resistance mice
Authors: Muller Cynthia Rodrigues , Americo Anna Laura Viacava , Fiorino Patricia , Evangelista Fabiana Sant'Anna 
Published: November 2023

Insulin resistance is associated with lipid accumulation in the kidney which leads to renal damage. We investigated the potential of aerobic exercise training (AET) to prevent renal damage in mice with diet‐induced insulin resistance. Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=7), cafeteria diet (CAF, n=7), chow‐fed trained (T, n=7), and cafeteria diet plus trained (CAFT=7). The standard chow diet contained 4% of kilocalories from fat, 55% from carbohydrate and 22% from proteins (Nuvilab®, Paraná, Brazil). The cafeteria diet contained 18.7% of kilocalories from fat, 56% from carbohydrate and 14.8% from proteins. PT was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from Faculty of Medicine of University of São Paulo (#18/2014). Cafeteria diet induced insulin resistance in CAF group compared to C group during insulin tolerance test, which was counteracted by AET in CAFT group. The glomerular filtration rate (GFR) increased by 88% in the CAF group compared to other groups. The water intake was lower in the CAF group (3.5 ± 0.3 mL) compared to the C (5.4 ± 0.5 mL), but there was no difference in urinary flow, urinary excretion of Na +, K +, Cl‐, total protein and urinary osmolarity. Histological analysis showed that CAF group increased intra‐renal lipid deposition (4.12 ± 0.48 %/area) compared to C group (1.70 ± 0.55 %/area), and that AET was able to prevent this increase in CAFT group (2.11 ± 0.51 %/area). There was a reduction in the Bowman's space in CAF group (104.4 ± 5.2 μm) compared to C group (154.3 ± 15.0 μm) and the AET prevented this decrease in CAFT (117.3 ± 5.3 μm). No changes were observed in the glomerular tuft area, however the CAF group showed a tendency to reduce Bowman's capsule area compared to C group (405.04 ± 21.23 vs. 470.7± 16.5 μm; p= 0.07). Protein expression of p‐AMPK increased in the CAFT group compared to the T group but there were no changes in t‐AMPK, t‐ACC, p‐ACC, PGC1‐α, SIRT‐1 expressions. In conclusion, our results showed that AET was efficient to prevent lipid deposition, the exacerbation of GFR and morphological impairments associated with insulin resistance. These responses may be associated, at least in part, with the increase in p‐AMPK in the kidney.Support or Funding InformationFAPESP # 2015/04948‐4.
YAP‐mediated mechanotransduction determines the podocyte's response to injury
Authors: Rinschen Markus , Grahammer Florian , Huber Tobias , Benzing Thomas , Schermer Bernhard 
Published: November 2023

Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological alterations as a result of cytoskeletal reorganizations. This becomes clinically apparent as proteinuria owing to leakage of the renal filter. The transcriptional co‐activators YAP/TAZ are tightly controlled through Hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury in vivo to induce YAP‐dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of podocytes in cell culture revealed decreased YAP/TAZ activity when cells were grown on stiff surfaces. Notably, culture on soft matrix or inhibition of stress fiber formation both allowed recapitulation of the damage‐induced YAP upregulation observed in vivo indicating a mechanotransduction‐dependent mechanism of YAP hyper‐activity. Yap overexpression enhanced the proteome‐wide expression of proteins related to extracellular matrix generation. Interestingly, increased expression of the bona fide YAP target CTGF was confirmed in renal biopsies from patients with glomerular disease. Consistently, genetic activation of YAP could induce mild proteinuria while pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease and damage‐induced mechanosignaling in vivo. Therefore, our findings suggest that perturbation of the mechanosensitive Hippo signaling pathway could be used as a therapeutic principle in podocyte disease.Support or Funding InformationDFG
Peri‐implantation Ozone Exposure Alters Uterine Artery Flow and Induces Fetal Growth Restriction in Rats
Authors: Miller Colette N , Ledbetter Allen D , Schladweiler Mette C , Richards Judy E , Wood Charles , Snow Samantha , Johnstone Andrew , Jaskot Richard , Henriquez Andres , Thompson Leslie C , Farraj Aimen , Hazari Mehdi , Dye Janice A , Kodavanti Urmila 
Published: November 2023

Epidemiological studies suggest a relationship between air pollutant exposures and various adverse pregnancy outcomes. Exposure to elevated ambient ozone levels during the first and second trimesters has been associated with increased risk for preeclampsia, gestational diabetes, and intrauterine growth restriction. As many of the adverse pregnancy outcomes are hypothesized to initiate from poor implantation, we sought to determine if an acute exposure to ozone during the implantation period would generate such outcomes later in pregnancy. Timed‐pregnant, Long‐Evans female rats were exposed to filtered air, 0.4ppm, or 0.8ppm ozone for 4 hours on each morning of gestational days 5 and 6. Tail cuff blood pressure and Doppler ultrasound of the uterine artery were measured following the phase of arterial remodeling on gestational days 15, 19, and 21. Rats were euthanized on gestational day 21 and offspring growth parameters were measured. While ozone exposure failed to impact maternal blood pressure at the times measured, multiple indices of blood flow in the uterine artery were adversely impacted as a result of early ozone exposure. Rats exposed to 0.8ppm ozone had increased uterine artery resistance index, systolic to diastolic ratio, pulsatile index, and end diastolic notching as pregnancy advanced compared to air controls. There was no evidence of systemic inflammation or kidney markers of preeclampsia in the dams. Ozone exposure decreased male and female offspring total weight, fat mass, and lean mass at the end of gestation. Further, 7 out of 9 dams exposed to 0.8ppm ozone during implantation had an average female offspring weight under the 10th percentile of air control pregnancies, suggestive of severe intrauterine growth restriction. Together these data suggest that peri‐implantation exposure to ozone adversely impacts uterine artery flow, which may have contributed to blunted fetal growth. These findings suggest a plausible biological mechanism for the epidemiological findings linking air pollutant exposure and adverse pregnancy outcomes. This abstract does not reflect US EPA Policy.Support or Funding InformationThis work was funded by the US EPA.