bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Selective Overexpression of ACE2 Attenuates Blood Pressure Response to Central Ang II: Potential Role of Nrf2
Authors: Ma Anyun , Gao Lie , Zucker Irving 
Published: June 2021

IntroductionEssential hypertension is characterized by increased neurohumoral activation. Central Angiotensin II (AngII) increases sympathetic outflow. Our previous studies showed dysfunctional central ACE2/Ang1‐7/Mas receptor axis and increased ACE in heart failure animals with increased sympathetic activation. Mice overexpressing the human isoform of ACE2 (synhACE2) in the brain exhibit reduced sympathetic nerve activity (SNA) and a reduction in central oxidant stress. However, the mechanism by which ACE2 overexpression alters neurohumoral outflow is unknown. Our preliminary experiments showed evidence of increased central Nrf2, a redox sensitive transcription factor, in synhACE2 mice with heart failure. Nrf2 promotes antioxidant enzyme expression, but the role of this pathway in the central regulation of sympathetic outflow in response to central Ang II has not been explored.HypothesisWe hypothesized that upregulation of central ACE2 inhibits the pressor response to AngII by a Nrf2–related, antioxidant effect.MethodssynhACE2+ mice and their synhACE2‐ littermates/wild type controls (n=3–7/group) were used to evaluate blood pressure, metabolic responses, Nrf2, antioxidant enzyme expression and oxidative stress in the brain during and following 2 weeks of intracerebroventricular (icv) AngII (100 ng/kg/min) infusion. In vitro experiments were carried out using Neuro 2A cells to assess Nrf2 translocation to the nucleus in response to AngII (100 nM/24 hrs) stimulation.Resultsicv AngII induced a significant increase in mean arterial blood pressure and polydipsia (Fig.1), as well as 24‐hour norepinephrine (NE) excretion. Brain selective overexpression of synhACE2 attenuated the blood pressure (95.2 ± 4.3 mmHg vs 125.4 ± 13.1 mmHg, p<0.05), polydipsia (11.3 ± 2.5mL/day vs 27.0 ± 2.0mL/day, p<0.05) and NE in response to central Ang II (Fig.1). The Mas receptor agonist Ang1‐7 and blockade (A779) had no effects on blood pressure or drinking responses following central Ang II infusion (Fig.1). In Neuro 2A cells, nuclear Nrf2 increased in response to AngII treatment.ConclusionsThese data indicate that the hypertensive effects of icv AngII are attenuated by brain selective overexpression of synACE2—most likely mediated by the effects of ACE2 on Ang II‐AT1R signaling. These data reinforce our previous finding that brain‐selective overexpression of ACE2 attenuates sympathetic nerve activity in CHF. The cell data show that AngII is capable of translocating Nrf2 to the nucleus, which is counteracted by common antioxidants, reflecting acute Nrf2 response to oxidative stress changes.Support or Funding InformationSupported by NIH grant P01 HL62222 and a UNMC pre‐doctoral fellowshipThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
γ‐secretase inhibitor DAPT mitigates cisplatin‐induced acute kidney injury by suppressing Notch1 signaling
Authors: Soni Hitesh M , Matthews Anberitha T. , Pallikkuth Sandeep , Gangaraju Rajashekhar , Adebiyi Adebowale 
Published: June 2021

Organ toxicity, including kidney injury, limits the use of cisplatin for the treatment of multiple human cancers. Hence, interventions to alleviate cisplatin‐induced nephropathy are of benefit to cancer patients. Recent studies have demonstrated that pharmacological inhibition of the Notch signaling pathway enhances cisplatin efficacy against several cancer cells. However, whether augmentation of the anti‐cancer effect of cisplatin by Notch inhibition comes at the cost of increased kidney injury is unclear. We show here that treatment of mice with cisplatin resulted in a significant increase in Notch ligand Delta‐like 1 (Dll1) and Notch1 intracellular domain (N1ICD) protein expression levels in the kidneys. N‐ [N‐ (3,5‐difluorophenacetyl) ‐L‐alanyl]‐S‐phenylglycine t‐butyl ester (DAPT), a γ‐secretase inhibitor reversed cisplatin‐induced increase in renal N1ICD expression and plasma or urinary levels of predictive biomarkers of acute kidney injury (AKI). DAPT also mitigated cisplatin‐induced tubular injury and reduction in glomerular filtration rate. Real‐time multiphoton microscopy revealed marked necrosis and peritubular vascular dysfunction in the kidneys of cisplatin‐treated mice which were abrogated by DAPT. Cisplatin‐induced Dll1/Notch1 signaling was recapitulated in a human proximal tubule epithelial cell line (HK‐2). siRNA‐mediated Dll1 knockdown and DAPT attenuated cisplatin‐induced Notch1 cleavage and cytotoxicity in HK‐2 cells. These data suggest that Dll1‐mediated Notch1 signaling contributes to cisplatin‐induced AKI. Hence, the Notch signaling pathway could be a potential therapeutic target to alleviate renal complications associated with cisplatin chemotherapy.Support or Funding InformationWe acknowledge a fellowship (to A. Adebiyi) from the O'Brien Center for Advanced Renal Microscopic Analysis (NIH‐NIDDKP30DK079312).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Diallyl trisulfide improves kidney function through alteration of fatty acid receptor expression in diabetic mice
Authors: Weber Gregory , Pushpakumar Sathnur , Sen Utpal 
Published: June 2021

Approximately 10% of the United States population suffers from diabetes causing diabetic nephropathy (DN) and eventually leading to renal failure. Fatty acids (FAs) are byproducts of gut microbiota and can regulate physiological process such as metabolism and inflammation as well as influenced through dietary supplements. Certain FA receptors have been shown to exert anti‐inflammatory effects in diabetes and other diseases; however, the role of these receptors in the kidney is not well defined. Diallyl trisulfide (DATS) is a major organosulfur component of garlic and is metabolized into hydrogen sulfide, an important gasotransmitter with noted cardiovascular and renal benefits. Whether DATS regulates FAs and their receptors in the kidney is unclear. In this study, we sought to determine if dietary supplementation with DATS improves kidney function by reducing inflammation through FA receptors in a Type‐II diabetic mouse model. Initial results showed improved kidney function of diabetic mice supplemented with DATS, as evidenced by an increase in glomerular filtration rate (GFR) as well as a lower resistive index (RI) of the renal artery compared to diabetic mice on a normal diet. The expression of short chain fatty acid receptor Gpr43 and long chain fatty acid receptor Gpr120 was altered in kidney of mice given DATS compared to untreated animals. In addition, Ptgs2, an enzyme implicated in the inflammatory response and can be inhibited by some naturally occurring FAs, was reduced in the kidney of diabetic mice supplemented with DATS. 16S sequencing showed DATS supplementation affected host gut microbiome composition, showing an enrichment in Verrucomicrobia and increased alpha diversity in diabetic mice on DATS diet. In conclusion, our data suggests FA receptors may play a role in the diabetic kidney by reducing inflammation with DATS supplementation, influencing the expression of these receptors, and improving kidney function. Further, a shift in the gut microbiome of diabetic mice toward that of non‐diabetic mice suggests a role for gut microbiota in DN and DATS supplementation may help delay or prevent the onset of this disease.Support or Funding InformationThis study was supported in part by U.S. National Institutes of Health (NIH) Grant DK104653 (U.S.) and American Heart Association Scientist Development Grant 15SDG25840013 (S.P.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Saturated Fatty Acids Stimulate Renal Inflammation‐Related Gene and Protein Expression by Activating the ERK Signaling Pathway
Authors: Zhao Xueying , Chen Xiaoming , George Jasmine , Zhang Yuanyuan , Cobbs Alyssa , Wang Guoshen , Li Lingyun , Emmett Nerimiah 
Published: June 2021

Diabetic nephropathy is increasingly recognized as a major contributor to renal dysfunction and kidney failure in obesity and type 2 diabetes. To identify the molecular mediators of kidney injury and dysfunction associated with metabolic syndrome with or without hyperglycemia, we compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO) and Zucker diabetic (ZD) rats. Compared to 20‐week‐old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with high‐degree albuminuria/proteinuria. Using cDNA microarray, we identified 25 inflammatory and fibrotic transcriptomes similarly changed in ZO and ZD kidneys, including kidney injury molecule‐1 (KIM‐1), secreted phosphoprotein‐1 (SPP‐1) and CD44. Immunostaining and Western blot analyses confirmed an increase in their protein levels in the kidney of ZO and ZD rats. Moreover, our in vitro cell culture study revealed that administration of saturated fatty acid palmitate resulted in an upregulation of KIM‐1, SPP‐1 and CD44 protein expression in primary tubular epithelial cells. Palmitate‐induced tubular inflammation and injury‐associated proteins were greatly attenuated in the presence of U0126, an inhibitor of extracellular signal‐regulated kinase 1/2 (ERK1/2). Taken together, our results demonstrate a stimulatory role of lipids for inflammation‐related gene and protein expression in the kidney, suggesting that lipotoxicity may play an important part in renal inflammation and nephropathy progression in metabolic syndrome associated with obesity and type 2 diabetes.Support or Funding InformationThis work was supported by the NIH 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.
Salt Sensing and Salt Response of Renal Neuropeptide FF Receptor 2
Authors: Villar Van Anthony M , Asico Laureano D , Wang Xiaoyan , Konkalmatt Prasad , Yang Jian , Gomes Jerald , Rozyyev Selim , Tiu Andrew C , Cuevas Santiago , Armando Ines , Jose Pedro A 
Published: June 2021

The causal role of dietary NaCl intake in the development of hypertension and salt sensitivity has long been recognized. The kidney sits at the fulcrum of maintaining an appropriate sodium balance and blood pressure homeostasis. As such, identifying new regulators of sodium balance in the kidney is crucial to understand the intricate mechanisms involved. Neuropeptide FF (NPFF) is a hormone expressed in the central nervous system that subserves nociception, hormonal modulation, and body temperature control. We now demonstrate for the first time that NPFF and its receptors, NPFF‐R1 and NPFF‐R2, are expressed in the kidney and endowed with pro‐hypertensive properties. The renal‐restricted bolus (1‐hr) or chronic infusion (7‐day) of NPFF increased blood pressure (*P<0.05, n=4/group) and decreased sodium excretion (UNaV; *P<0.05, N=4/group) in C57Bl/6 mice. This tubular effect was due solely to NPFF‐R2 since its silencing resulted in ~3‐fold increase in UNaV, unlike NPFF‐R1 silencing which did not affect UNaV. Therefore, we further explored the changes in NPFF‐R2 expression or activity in response to changes in salt. We now report that we have newly identified a “Sodium Response Element” (SRE), a homolog of “Dehydration‐Responsive Element” (“TACCGACAT”) in Arabidopsis thaliana genome, at the NPFF‐R2 promoter ~ 2.3 Kb upstream of the transcription start point. Exposing human renal proximal tubule cells (hRPTCs) from normal (145 μM NaCl) to low (90 μM NaCl) sodium concentration resulted in increased promoter activity (~2.5‐fold, *P<0.05, vs. DSRE, 3/group; via luciferase activity) and increased mRNA and protein expression of NPFFR2 (*P<0.05, 3–4/group; 0–8 hr). Exposure of hRPTCs from normal to high (175 μM NaCl) sodium concentration was accompanied by a reduction in promoter activity (−0.5‐fold, *P<0.05), and a decrease in mRNA and protein expression of NPFFR2 (*P<0.05, 0–8 hr). Moreover, there was a markedly increased co‐immunoprecipitation between pro‐hypertensive NPFF‐R2 and anti‐hypertensive dopamine D1 receptor, resulting in increased antagonism between the two receptors on cAMP response and sodium transport (*P<0.05, vs. fenoldopam or NPFF treatment [1 mM/30 min], 4/group). Lastly, exposure to high salt concentration resulted in greater co‐immunoprecipitation of NPFF‐R2 with Gαi3 and none with Gαs (“Gα switch”), which may explain its pro‐hypertensive activity. NPFF, via NPFF‐R2, may be a crucial determinant of sodium balance and blood pressure homeostasis and thus, may be an important target for new pharmacological and biological intervention.Support or Funding InformationR01DK039308, R01HL092196, and P01HL074940This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeted inhibition of mitochondrial ROS maintains TFAM and mitochondrial DNA homeostasis in acute kidney injury
Authors: Zhao Meng , Liu Shunyun , Wang Chengshi , Cui Danli , Li Lan , Yuan Yujia , Chen Younan , Lu Yanrong , Liu Jingping 
Published: June 2021

BackgroundAcute kidney injury (AKI) is a serious worldwide health issue with high mortality and morbidity, and oxidative stress / mitochondrial dysfunction have been recognized as key features of AKI. Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondria DNA (mtDNA) transcription and replication, which maintains the cellular mitochondrial redox and energy homeostasis in various physiological conditions, but its alteration in AKI is not complete clear. In this study, we aim to investigate the effect of mitochondrial ROS (mtROS) on TFAM signaling and mtDNA damage in AKI.MethodsIn vitro, human proximal tubule epithelial cell lines (HK‐2) were incubated under hypoxia/reoxygenation (H/R) condition, and cellular mtROS were specifically eliminated by mitochondria‐targeted antioxidant Mito‐Tempo (MT). The changes of intracellular ROS, TFAM, mitochondrial biogenesis, mtDNA copy number, cell apoptosis and inflammation in HK2 cells were analyzed. In vivo, AKI mice were induced by renal ischemia/reperfusion (I/R) injury and treated with MT, and the changes of renal function, tubular injury, inflammation, mitochondrial function, mtROS, ATP production, and mtDNA level were measured.ResultsIn vitro, H/R condition induced mtROS with declined TFAM and mtDNA injury, as well as increased inflammation and apoptosis in HK2 cells. By contrast, targeted inhibition of mtROS restored TFAM, mtDNA copy number and mitochondrial biogenesis (PGC1α), and reduced proinflammatory cytokines (IL‐1β/TNF‐α) and pro‐apoptotic factors (FAS) expression in HK2 cells. However, the cytoprotective role of mtROS inhibition on mtDNA and mitochondrial biogenesis was diminished in HK2 cells when knockdown of TFAM by siRNA, In vivo, targeted inhibition of mtROS also reduced the levels of serum BUN/CREA, necrotic tubules number, tubular apoptosis and renal inflammation in AKI mice. Moreover, targeted inhibition of mtROS rescued the TFAM and mtDNA damage with improved mitochondrial morphology, ATP production and mtDNA copy number in kidney of AKI mice.ConclusionThis study highlights that TFAM plays an essential role in maintaining mitochondrial redox homeostasis, and mtROS induce renal dysfunction via disturbing TFAM and mtDNA, thus targeted inhibition of mtROS is a promising therapy for AKI.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.
Treatment with lisinopril slows the early progression of proteinuria in obese Dahl salt‐sensitive rats independent of lowering arterial pressure and GFR
Authors: Pennington Alyssa P. , Poudel Bibek P. , Shields Corbin A. , Thompson Willie , Williams Jan M. 
Published: June 2021

Prepubertal childhood obesity (PPO) has emerged as an epidemic and major health problem in the United States. Previous studies have demonstrated that patients who developed obesity prior to puberty are at higher risk of developing progressive proteinuria and chronic kidney disease. Moreover, the early stages of renal injury associated with obesity is characterized with renal hyperfiltration. Recently, we observed the early development of renal injury in the obese Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in GFR. Furthermore, these renal abnormalities develop prior to puberty (6 weeks of age) and independent of hyperglycemia and elevations in arterial pressure. The standard care of treatment for obese children with hypertension and increased risk of renal disease is an angiotensin converting enzyme inhibitor (ACEi) such as lisinopril. Therefore, the current study examined whether treatment with lisinopril prevents the early development of proteinuria in the SSLepRmutant strain. Experiments were performed on four week‐old SSWT and SSLepRmutant rats that were either treated with vehicle or lisinopril (20 mg/kg/day, drinking water) for four weeks. We did not observe any differences in MAP between SSWT and SSLepRmutant rats (156±6 and 163±7 mmHg, respectively). While treatment with lisinopril markedly reduced MAP in SSWT rats (108±4 mmHg), lisinopril had no effect on MAP in the SSLepRmutant strain (146±7 mmHg). Proteinuria was significantly higher in the SSLepRmutant strain compared to SSWT rats at baseline (105±19 and 17±5 mg/day, respectively) and remained elevated over the course of the study (400±48 and 60±9 mg/day, respectively). Treatment with lisinopril significantly decreased the progression of proteinuria by 68% in SSWT rats (19±3 mg/day) and 40% in SSLepRmutant rats (242±31 mg/day). GFR was elevated in the SSLepRmutant strain compared to the values measured in the SSWT rats (4.80±0.50 vs. 3.87±0.48 mL/min, respectively). Interestingly, lisinopril treatment had no effect on GFR in both strains. These data suggest that obese SSLepRmutant rats develop progressive proteinuria associated with hypertension and elevations in GFR, and treatment with lisinopril blunted the progression of proteinuria independent of lowering GFR and arterial pressure during PPO.Support or Funding InformationThis work was supported by GM104357 and DK109133.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Depletion of macrophages with clodronate partially reduces the progression renal injury in obese Dahl salt‐sensitive rats during prepubertal obesity
Authors: Poudel Bibek , Shields Corbin A. , Pennington Alyssa , Cornelius Denise C. , Williams Jan M. 
Published: June 2021

Prepubertal obesity (PPO) is now considered a risk factor for the development of proteinuria and renal injury in children. Recently, we reported that, prior to puberty, Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) rats display proteinuria and renal injury as early as 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. Moreover, the early development of renal injury was associated with an increase in the renal infiltration of macrophages in the SSLepRmutant strain compared to their lean SSWT counterparts (39±14 vs. 11±3 % gated, respectively; p<0.05 vs. SSWT). Therefore, the current study examined whether depletion of macrophages with clodronate would reduce renal injury in the SSLepRmutant strain during PPO. Four week‐old SSWT and SSLepRmutant rats were separated into four groups (n=4/group): (1) SSWT and (2) SSLepRmutant rats treated with vehicle‐PBS and (3) SSWT and (4) SSLepRmutant rats treated with clodronate (50 mg/kg, i.p., twice/week) for 4 weeks. While administration of clodronate did not have an effect in SSWT rats, clodronate significantly depleted macrophages in the kidneys of SSLepRmutant rats compared to vehicle‐treated rats without altering the monocyte population (8±4 versus 33±10 % gated, respectively; p<0.05 vs. vehicle). At baseline, protein excretion was significantly higher in SSLepRmutant rats compared to SSWT rats (70±14 vs. 10±3 mg/day, respectively; p<0.05 vs. SSWT) that further increased over the course of the study (335±82 vs. 45±14 mg/day, respectively; p<0.05 vs. SSWT). Clodronate had no effect on the progression of proteinuria or renal histopathology in SSWT rats. After 2 weeks of treatment with clodronate, protein excretion was markedly reduced in the SSLepRmutant strain (86±36 vs. 200±35 mg/day; p<0.05 vs. vehicle). However, after 4 weeks of treatment, the effect of clodronate was no longer observed in the SSLepRmutant strain (270±90 vs. 335±82 mg/day). The kidneys from SSLepRmutant rats displayed glomerular injury with increased mesangial expansion and renal fibrosis versus SSWT rats. Interestingly, treatment with clodronate had no effect on glomerular injury but significantly decreased renal fibrosis in the SSLepRmutant strain compared to their vehicle‐treated obese counterparts. Overall, these data indicate that the early development of renal injury in the SSLepRmutant strain is associated with macrophage infiltration, which can be blunted by chronic macrophage depletion.Support or Funding InformationThis study was supported by GM104357 and DK109133.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.