bluuebunny/crossref_metadata_2025_split huggingface dataset:
123I‐MIBG scintigraphy suggests functional sympathetic reinnervation in human renal allografts (687.1)
Authors: Dobrowolski Linn , Verberne Hein , ten Berge Ineke , Bemelman Frederike , Krediet C.T. 
Published: June 2021

After kidney transplantation, sympathetic renal nerves may reinnervate the allograft, but its functional significance is unknown.123I‐metaiodobenzylguanidine (123I‐MIBG) scintigraphy determines organ specific sympathetic innervation (uptake) and activity (washout rates, WORs). Therefore we applied 123I‐MIBG scintigraphy to assess the functionality of sympathetic nerves in human renal allografts.We studied 5 patients with a median allograft survival of 20 years (range 11‐36), creatinine clearance 89 ml/min (56‐118). Their immunosuppressive drug regimen consisted of azathioprine and prednisolone. None of them was treated with either alpha‐ or beta‐blocking agents.After intravenous administration of 185 MBq 123I‐MIBG, scintigrams were made at 15 min and 4 hr postinjection (p.i.) and a CT scan was made for anatomical localization of the tracer. Uptake was calculated as % of injected dose 123I‐MIBG. WORs in the myocardium, native left kidney and renal allograft were deducted from 15 min and 4 hr scintigrams. For WORs the relative uptake was used in relation to non‐specific uptake (i.e. mediastinum). Median % injected dose uptake in the myocardium, native left kidney and renal allograft was 3.7, 5.5, 3.8% at 15min p.i. and 3.3, 4.8 and 1.6% at 4hr p.i. respectively. WORs were 4.8, 6.7 and 26%.These data suggest some functional sympathetic reinnervation in long surviving human renal allografts. The use of renal 123I‐MIBG scintigraphy should be validated and functional significance of this sympathetic reinnervation in renal allografts will be further studied.Grant Funding Source: Dutch Kidney Foundation (IP 11‐40)
Capsaicin‐mediated selective afferent renal nerve denervation: effects on intrarenal responses to bradykinin and adenosine in conscious Sprague‐Dawley rats (687.2)
Authors: Wainford Richard 
Published: June 2021

Aim: It has been reported that capsaicin evokes selective denervation of the renal afferent nerves in rats as confirmed by IHC. We assessed the efficacy of capsaicin‐mediated afferent denervation in preventing the physiological responses to activation of the renal afferent nerves.Methods: Conscious Sprague‐Dawley rats implanted with an ICV cannula, having undergone sham (S) or renal afferent nerve denervation (ADNX) (capsaicin 33mM), received IV and IR infusions of bradykinin (BK) (5‐40 μg/kg/min) and adenosine (A) (2‐12 μg/min). All animals then received ICV guanabenz (50ug) (N=4/gp). HR, MAP and sodium excretion were continuously monitored.Results: IR BK dose‐dependently increased MAP and HR in sham animals and had no effect on MAP or HR in ADNX rats (BK 40 μg/kg/min; peak ΔHR [bpm] S +61±8 vs ADNX ‐5±3, P<0.05; peak ΔMAP [mmHg] S +19±3 vs ADNX +0.6±2, P<0.0.5). IV BK did not alter MAP or HR at any dose tested in S or ADNX rats. IR, but not IV, adenosine evoked a dose‐dependent increase in natriuresis in sham animals, a response that was abolished following ADNX (A 12 μg/min; peak ΔUNaV [ueq/min] S +18.7±3 vs ADNX +2±0.4, P<0.05). In both sham and ADNX rats, ICV guanabenz evoked profound bradycardia, hypotension and natriuresis (guanabenz 50 μg; peak ΔUNaV [μeq/min] S +13.4±1 vs ADNX +12.8±1).Conclusion: These data provide compelling evidence that the recently described technique of capsaicin mediated afferent renal denervation prevents the physiological responses to intrarenal administration of established activators of the renal afferent nerves. Further, central α2‐adrenoceptor activation evoked a profound natriuretic response mediated by suppression of efferent nerve activity in sham and ADNX rats. This indicates the presence of viable and functional renal efferent nerves following ADNX. Collectively these data demonstrate it possible to selectively denervate renal afferent nerves without affecting the function of the renal efferent nerves.Grant Funding Source: Support by R01HL107330 & K02HL112718A1
Enzamin improves adipose tissue inflammation with impaired adipocytokine expression and insulin resistance in obese mice (688.1)
Authors: Matsuo Osamu , Tamura Yukinori , Yano Masato , Kawao Naoyuki , Ueshima Shigeru , Kaji Hiroshi 
Published: June 2021

Aim: Effects of Enzamin, which is a product from Bacillus subtilis AK and Lactobacillus, on obesity‐related metabolic disorders in obese db/db mice were examined to explore a novel agent for the prevention of insulin resistance.Methods and Results: Db/db mice were treated with water containing Enzamin (0.1% and 1.0%) for 8 weeks from 6 weeks of age. Enzamin treatment at 1.0% significantly decreased the fasting plasma glucose, serum total cholesterol and triglyceride levels in db/db mice. Furthermore, insulin resistance was improved by the treatment of db/db mice with Enzamin. Enzamin suppressed macrophage accumulation and inflammation in the adipose tissue and increased serum adiponectin in db/db mice. Enzamin also significantly suppressed the expression of NADPH oxidase subunits, suggesting an anti‐oxidative effect of Enzamin in the adipose tissue. Enzamin increased the mRNA expression of GLUT4 and carnitine palmitoyltransferase 1a in muscle of db/db mice. Further, in vitro experiments demonstrated that the lipopolysaccharide‐induced inflammatory reaction was significantly suppressed by Enzamin in macrophages.Conclusion: Our data indicates that Enzamin can improve insulin resistance by ameliorating impaired adipocytokine expression, presumably through its anti‐inflammatory action, and that Enzamin possesses a potential for preventing metabolic syndrome.Grant Funding Source: None
Elevated NOX1 determines oxidant load obesity and is reduced with increases in muscle mass (688.6)
Authors: Qiu Shuiqing , Mintz James , Salet Christina , Weihong Han , Chen Feng , Yu Yanfang , Su Yunchao , Fulton David , Stepp David 
Published: June 2021

Increases in muscle mass, as observed with exercise, are positive influences of cardiovascular health. Recent studies from our lab have shown the increase muscle mass via deletion of myostatin improves vasodilation but the underlying mechanisms are unknown. Improving insulin resistance has been shown to improve oxidant stress, specifically via expression of NOX1. Hypothesis: Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice via reducing NOX‐mediated oxidant stress in the endothelium. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%). Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrate superoxide‐mediated impairment of ACh‐induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved ACh‐induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L‐NAME. PGI2 and EDHF mediated vasodilation were unaffected by obesity or myostatin deletion. Treatment with sepiapterin (1×10‐6 mol/L, a precursor of the nitric oxide synthase cofactor tetrahydrobiopoterin) or GKT(1×10‐6 mol/L, NADPH oxidase inhibitor) restored impaired vasodilation in obese mice. Elevated oxidized DNA/RNA was observed in the endothelium of obese mesenteric arteries, and this elevation was blunted by myostatin deletion. NOX1 expression was increased in the endothelium of obese mice mesenteric arteries, which was reversed by myostatin deletion. Taken together, these data suggest that increasing muscle mass by deletion of myostatin improves NO‐mediated vasodilation in obese mice; this vasodilation improvement is mediated by down regulation of NOX1 in the endothelium.Grant Funding Source: Supported by NIH R01 HL092446, R21 HL098829 and AHA‐GSA 13PRE14680055
ORAI store‐operated calcium channels are associated with proximal renal tubule dysfunction in diabetic nephropathy (689.13)
Authors: Garcia‐Vaz Eliana , Chen Gui‐Lan , Bhandari Sunil , Daskoulidou Nikoleta , Zeng Bo , Jiang Hongni , Gomez Maria F. , Atkin Stephen L. , Xu Shang‐Zhong 
Published: June 2021

Proteinuria is not only an early sign of diabetic nephropathy (DN) but also contributes to the development and progression of the disease. The molecular mechanisms underlying proteinuria remain unclear. Here we explored the role of ORAI store‐operated calcium channels in DN. RT‐PCR and western blot experiments demonstrated expression of all ORAI isoforms (ORAI1‐3) in human kidney. ORAI channels were preferentially expressed in the proximal tubules and intrarenal arteries as assessed by immunohistochemistry; and ORAI channel expression was down regulated in type 1 diabetic patients with DN. Using primary human proximal tubular cells, we showed that high glucose (25 mM) significantly reduced ORAI1‐3 mRNA and protein expression, whereas insulin increased channel expression. Conversely, blockade of insulin signaling using tyrphostin A23 or wortmannin reduced channel expression. We identified a current evoked by thapsigargin and inositol 1,4,5‐trisphosphate (IP3 ) in the proximal tubular cells, sensitive to diethylstilbestrol (DES) and 2‐APB. Using ORAI1‐3/STIM1 overexpressing systems, we found that DES and BTP2 inhibited all three ORAI channels, while 2‐APB selectively blocked ORAI1 and ORAI2, but stimulated ORAI3 channels. Pharmacological inhibition of ORAI channel activity by DES, 2‐APB or BTP2, or silencing of ORAI expression by small interfering RNA significantly reduced FITC‐albumin uptake in proximal tubular cells. These results suggest that down‐regulation of ORAI channel expression or inhibition of channel activity leads to impaired protein reabsorption in the proximal tubules, representing a novel mechanism underlying diabetic proteinuria.Grant Funding Source: British Heart Foundation, Leverhulme Trust, China Scholarship Council; Swedish Research Council
High fat diet decreases fractional sodium excretion and increases systolic blood pressure via angiotensin II‐mediated increase in epithelial sodium channel abundance (689.2)
Authors: Minas Jacqueline , Nakano Daisuke , Awayda Mouhamed , Nishiyama Akira , Ortiz Rudy 
Published: June 2021

High fat diet (HFD) accelerates diabetic nephropathy via impaired sodium (Na+) regulation and improper insulin signaling. Angiotensin II (AngII) receptor (AT1) blockers (ARBs) ameliorate insulin resistance, antinatriuresis, and elevated systolic blood pressure (SBP). However, the renoprotective effects of ARB during HFD remain elusive. To assess the role of AT1 activation to improper Na+ handling in a model of metabolic syndrome (OLETF) supplemented a HFD, seven groups were studied: 1) untreated, lean LETO, 2) LETO HFD (62% fat), 3) LETO HFD + ARB (10 mg olmesartan/kg/d), 4) untreated, obese OLETF, 5) OLETF HFD, 6) OLETF ARB, and 7) OLETF HFD + ARB. ARB reduced SBP in both OLETF (151 ± 3 mmHg vs 114 ± 3) and OLETF HFD (151 ± 2 vs 101 ± 6). Creatinine clearance decreased 35% in OLETF compared to LETO and increased 2‐fold in OLETF HFD compared to OLETF. Fractional excretion of Na+ (FENa) decreased 40% in OLETF compared to LETO. HFD decreased FENa 50‐75%, whereas ARB increased FENa in all cases. HFD increased urine aldosterone excretion 35% in both LETO and OLETF. Also, HFD increased potassium FE (FEK) 2 and 4‐fold in OLETF and LETO, respectively. ARB reduced FEK levels in all groups. Also, HFD increase levels of cleaved γ‐Epithelial Na+ Channel (ENaC) content 31% in OLETFs. Collectively, these data indicate that HFD exacerbates impaired renal function by increased ENaC abundance during Ang II‐mediated hypertension.Grant Funding Source: Supported by: NIH MHIRT and USDA Minority Research Training Fellowship
Contrasting differences of chronic endothelin A receptor blockade during the progression of renal injury in type‐1 and type‐2 diabetic nephropathy (689.3)
Authors: Spires Denisha , White Tiffani , Taylor Lateia , Williams Jan 
Published: June 2021

Contrasting differences of chronic endothelin A receptor (ETA) blockade during the progression of renal injury in type‐1 and type‐2 diabetic nephropathy
Denisha Spires1, Tiffani White2, Lateia Taylor2 and Jan M. Williams2. 1Tougaloo College, Tougaloo, MS, 2Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS 39216 The endothelin (ET) system has been shown to play an important role in the development and progression of diabetic nephropathy (DN) via the endothelin A (ETA) receptor. Preliminary studies from our laboratory indicate that the induction of diabetes (STZ, 50 mg/kg, i.p.) in Dahl salt‐sensitive (STZ‐SS) rats promotes the development DN that was associated with an increase in ET‐1 excretion. Therefore, the present study examined whether chronic ETA blockade with ABT‐627 prevents the progression of renal injury in STZ‐SS rats with pre‐existing renal disease. After 6 weeks of ABT‐627 (5mg/kg/day) treatment, proteinuria was markedly decreased in ABT‐627 treated STZ‐SS rats versus vehicle treated rats without any changes in arterial pressure (310±32 vs. 517±68 mg/day, respectively). The degree of glomerulosclerosis and renal interstitial fibrosis was significantly reduced in the kidneys of ABT‐627 treated STZ‐SS rats compared to vehicle STZ‐SS rats. We next determined whether treatment with ABT‐627 would be beneficial in a type‐2 diabetic model (T2DN rat) with pre‐existing renal injury. In contrast to the STZ‐SS study, ABT‐627 had no effect on the progression of renal injury in T2DN rats. In conclusion, these data indicate that treatment with an ETA receptor blocker prevents the progression of renal injury in type‐1 diabetes but not in type‐2 diabetes.Grant Funding Source: Supported by P20GM104357
What makes SGLT2 inhibition so effective in lowering blood glucose in diabetes? (689.5)
Authors: Gerasimova Maria , Rose Michael , Koepsell Hermann , Masuda Takahiro , Mayoux Eric , Thomson Scott , Rieg Timo , Vallon Volker 
Published: June 2021

Studies in knockout mice indicated that, in euglycemia, the sodium glucose cotransporters SGLT2 and SGLT1 reabsorb 97 and 3% of filtered glucose, respectively. The SGLT1 contribution is enhanced to 40‐50% during genetic or pharmacologic SGLT2 inhibition. Here we show that the SGLT2 inhibitor empagliflozin (in diet for 15 weeks; 60‐80 mg/kg/d) strongly lowered blood glucose (BG) in type 1 diabetic Akita mice (means of 187‐237 vs. 517‐535 mg/dl in vehicle group; n=10‐13/group). In steady‐state, empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose (due to lowering BG and preventing glomerular hyperfiltration [determined in awake mice by FITC‐inulin plasma kinetics; GFR means of 255 vs. 397 µl/min]) balanced the inhibition of glucose reabsorption. Akita‐diabetes, empagliflozin alone, and Akita+empagliflozin similarly increased renal membrane SGLT2 expression (by 38‐56%) but reduced the expression of SGLT1 (by 33‐37%) vs vehicle‐treated wild‐type mice (WT). Phosphoenolpyruvate carboxykinase (PEPCK) is a principal gluconeogenic enzyme and regulated by gene transcription. Renal PEPCK mRNA expression was elevated by 60% in Akita versus WT mice and normalized by empagliflozin. All mentioned differences were statistically significant. We conclude that the diabetes‐induced changes in renal SGLT2/SGLT1 expression facilitate the blood glucose lowering potential of SGLT2 inhibition by upregulating the target protein and downregulating compensating SGLT1 (the latter is also observed in mice lacking SGLT2 and prevents excessive glucose uptake in late proximal tubule). In addition, SGLT2 inhibition may attenuate diabetes‐induced renal gluconeogenesis.Grant Funding Source: Supported by NIH grants R01DK56248, R01HL94728, P30DK079337
Hydrodynamic delivery of mitochondrial genes in vivo protects against moderate ischemia‐reperfusion injury in the rat kidney (690.17)
Authors: Corridon Peter , Rhodes George , Zhang Shijun , Bready Devin , Xu Weimin , Witzmann Frank , Atkinson Simon , Basile David , Bacallao Robert 
Published: June 2021

Ischemic preconditioning is well known to afford protection against subsequent episodes of ischemia/reperfusion (I/R) in multiple organs, including the kidney, but the mechanisms involved are not fully understood. We proposed that ischemic preconditioning results in an altered mitochondrial proteome that confers resistance to subsequent I/R injury. We subjected rats to moderate ischemic injury and used liquid chromatography – mass spectroscopy (LC/MS) to analyze the proteome of kidney cortical mitochondria isolated following 14 days of recovery from I/R. The expression of several proteins was elevated following preconditioning, and two were selected for further analysis: Isocitrate dehydrogenase 2 (IDH2) and a member of the sulfotransferase family (SULT1A1). The effect of increased expression of these proteins was evaluated by using hydrodynamic gene delivery of plasmid vectors to overexpress each protein. Strikingly, hydrodynamic delivery of IDH2 and SULT1A1 genes attenuated the peak in serum creatinine following I/R injury induced by a 40 minute bilateral clamp by 82% and 74% respectively, and by 66% and 49% respectively following I/R in uninephrectomized rats. Histological analysis showed significantly reduced proximal tubule damage. We evaluated mitochondrial respiratory chain activity in vivo using 2‐photon fluorescence microscopy and the potential‐sensitive dye TMRM, and using biochemical assays in vitro, and showed that mitochondrial respiration was maintained in animals that received hydrodynamic delivery of either gene relative to controls. In conclusion, our study supports the concept that adaptive changes in mitochondria can confer protection to ischemic damage, and the utility of hydrodynamic gene delivery as a method of manipulating kidney function.Grant Funding Source: Supported by NIH/NIDDK DK088934
Loss of alpha(E)‐catenin increases cisplatin nephrotoxicity (691.2)
Authors: Wang Xinhui , Grunz‐Borgmann Elizabeth , Nichols LaNita , Parrish Alan 
Published: June 2021

Cisplatin is one of the most potent and widely used antineoplastic drugs. However, the use of cisplatin is dramatically limited by its side effect, nephrotoxicity. Evidence has shown that there is an increased incidence and severity of acute kidney injury (AKI) in the elderly. We previously reported a dramatic decrease of α‐catenin expression in proximal tubular epithelium of aged kidney. We hypothesize that loss of α(E)‐catenin increases susceptibility to cisplatin. To study the effects of reduced α‐catenin, shRNA knock‐down of α(E)‐catenin (C2) was generated in NRK‐52E cells; NT3 is the non‐targeted control. Confluent cultures of cells were challenged with cisplatin (50, 100, 150 μM) for 24 hr and C2 cells exhibited a significant loss of viability at all concentrations as compared with NT3 cells. Interestingly, the expression of α(E)‐catenin was further decreased in both cell lines. Importantly, higher caspase 3/7 activity was observed in C2 cells than NT3 cells after cisplatin treatment indicating the increased susceptibility may be due to apoptosis. To elucidate the mechanism of increased apoptosis in C2 cells, we performed RNA sequencing and identified that CYFIP2, a pro‐apoptotic gene, had 6.44 fold higher expression in C2 cells than NT3 cells. This finding was confirmed by qPCR. Taken together, these results suggest that loss of α(E)‐catenin may increase cisplatin‐induced nephrotoxicity via apoptosis.Grant Funding Source: Supported by NIH RO1AAG034154
Direct effect of glucagon‐like peptide‐1 on the autoregulatory response of the afferent arteriole (692.2)
Authors: Sorensen Charlotte , Jensen Elisa , Poulsen Steen , Holst Jens , Holstein‐Rathlou Niels‐Henrik 
Published: June 2021

It has become clear that glucagon‐like peptide‐1 (GLP‐1) has many effects and the GLP‐1 receptor is expressed in many tissues outside the pancreas. GLP‐1 increases renal blood flow (RBF), glomerular filtration rate and sodium and water excretion. The aim of this study was to examine expression of the GLP‐1 receptor in the renal vasculature and assess the effects of GLP‐1 in the afferent arteriole.The GLP‐1 receptor was localized using 125I‐GLP‐1 in kidney slices. In the isolated juxtamedullary nephron preparation, renal perfusion pressure was increased in steps and changes in afferent arteriolar diameter were measured before and after perfusion with GLP‐1. In vivo experiments were performed on rats monitoring blood pressure (BP), RBF and urine flow. GLP‐1 was infused directly into the kidney before and after infusion of the GLP‐1 receptor blocker Exendin9‐39 and indomethacin and L‐NAME.Strong binding of 125I‐GLP‐1 was found in the vascular smooth muscle cells in afferent arterioles. Perfusion with GLP‐1 in isolated kidneys completely abolished the autoregulatory response of the afferent arteriole. Intrarenal infusion of GLP‐1 increased BP, RBF and urine flow significantly in rats. Heart rate and plasma renin were unchanged. The effect on RBF was inhibited by Exendin9‐39 whereas the increase in BP and urine flow was still present. Infusion of indomethacin and L‐NAME did not change the GLP‐1 effect on BP, RBF or urine flow.
Intravital imaging of afferent arteriole calcium dynamics (692.7)
Authors: Riquier‐Brison Anne , Burford James , Sequeira‐Lopez Maria Luisa , Gomez R. Ariel , Peti‐Peterdi Janos 
Published: June 2021

The afferent arteriole (AA) of the glomerulus is the most critical resistance vessel in the autoregulation of renal blood flow and glomerular filtration rate. Calcium dynamics of the AA, including myogenic contraction and the calcium wave of tubuloglomerular feedback (TGF) have been studied in vitro, however their relevance to in vivo conditions is not known. We aimed to directly visualize the dynamics of intracellular calcium [(Ca2+)i] in cells of the AA in vivo in the intact living kidney. Multiphoton imaging of the kidney was performed <2 weeks after unilateral ureter obstruction (UUO) in mice expressing the genetically encoded calcium indicator GCaMP3 in cells of the renin lineage (Ren1dCre/GCaMP3fl). Myogenic tone of the AA was observed as regularly oscillating AA constrictions, once in every 7.1±0.2 seconds (n=19) associated with minor elevations in AA vascular smooth muscle cells (VSMC) (Ca2+)i. In contrast to the low and even GCaMP3 fluorescence along the length of the AA, high baseline and ∆(Ca2+)i were observed in 1‐2 VSMCs at the glomerular entrance which appeared to function as sphincter cells. Laser‐induced stimulation of macula densa (MD) cell permeability triggered robust, 1.9±0.2‐fold increases in AA VSMC baseline (Ca2+)i and augmented the AA myogenic responses (n=11). Focal MD stimulation triggered a propagating calcium wave along the AA towards proximal segments (with a speed of 6.8±0.9 um/s, n=5) and into the glomerular mesangium (1.2±0.1 um/s). We concluded that AA sphincter cells and MD‐derived signals have the most robust effects on AA (Ca2+)i dynamics and contractility in vivo.Grant Funding Source: Supported by AHA