bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased TRF2 binding likely limits telomere uncapping in older human arteries despite age‐related telomere attrition
Authors: Morgan Garrett , Ives Stephen J , Lesniewski Lisa A , Cawthon Richard M , Andtbacka Robert HI , Noyes R Dirk , Richardson Russel S , Donato Anthony J 
Published: June 2021

Telomeres are DNA repeats that cap chromosome ends and prevent premature senescence. Capping is maintained by two key regulatory proteins; telomere repeat binding factor 2 (TRF2) and telomerase (TERT). Mean telomere length (mTL) and TERT activity decline with age in various tissues, but little is known regarding arterial tissue. Ninety‐seven human arteries were obtained during outpatient surgeries and mTL (qPCR) as well as telomere localization of TRF2, TERT and phosphorylated H2A.X (p‐H2A.X), a marker of uncapping, were measured (chromatin‐IP). mTL declined progressively with age, as younger adult (YA ≤ 40 yrs) mTL was 22% higher than middle‐age (MA: 41–59 yrs), and MA was 10% higher than older (OA ≥ 60 yrs) mTL (all p ≤ 0.05). TRF2 localization was higher in OA than in YA (p = 0.02), while TERT and p‐H2A.X localization were not different with age (all p ≥ 0.24). Shortest to longest mTL was separated into quartiles (Q1–4) to assess uncapping with mTL attrition. p‐H2A.X and TRF2 localization were higher in Q1 than in Q2–4 (all p ≤ 0.01). OA comprised 48% of Q1 and 9% of Q4, suggesting that age contributes to, but doesn't fully explain, mTL‐related uncapping. These results demonstrate that mTL declines progressively across age‐groups in human arteries despite similar TERT localization, but indicate compensatory increases in TRF2 binding may prevent uncapping in older arteries.Support: NHLBI‐HL09183, U. Center on Aging
Elucidating the role of a renal proximal tubule‐specific olfactory receptor
Authors: Shepard Blythe D , Cheval Lydie , Doucet Alain , Pluznick Jennifer L 
Published: June 2021

Olfactory receptors (ORs) are seven transmembrane domain G protein‐coupled chemosensors that serve as sensors of smell in the nose. Recently, studies have found that ORs and other chemosensors are also expressed outside of their native tissues where they have important functions. We have previously reported that OR signaling plays a role in the kidney, and that Olfr1393 is present in the kidney (PNAS 2009). Using reverse‐transcribed RNA from microdissected renal segments, we found that Olfr1393 is exclusively expressed in all three segments of the proximal tubule (S1, S2 and S3, n=3). Olfr1393, like the majority of ORs, is an “orphan receptor” with no known ligand. To screen for ligands, Olfr1393 must first be expressed on the plasma membrane (PM). However, most ORs are retained in the ER when expressed in HEK293T cells. We have recently cloned this renal OR and found that it can traffic to the PM when coexpressed with Receptor Trafficking Protein. Using a comprehensive screening approach, we have found that Olfr1393 detects cyclic molecules containing a carbonyl group. There are a vast array of physiological chemicals that are derived from this basic unit including bile acids, vitamins and steroid hormones, all of which play important roles in the kidney. We are currently focusing on defining the full complement of ligands for Olfr1393, and understanding the physiological role that this OR plays in the kidney.Funding NIDDK
Fructose as a modulator of proximal tubule (PT) H+ transport
Authors: Queiroz-Leite Gabriella Duarte , Crajoinas Renato O. , Neri Elida A. , Bezerra Camila N. A. , Girardi Adriana C. C. , Rebouças Nancy A. , Malnic Gerhard 
Published: June 2021

High fructose (F) intake adversely affects the kidneys. This study was outlined to investigate F effects on NHE3 activity. Microperfusion showed that 2 and 3mM F stimulate JHCO3‐(nmol/cm2 × s) (2.87 ± 0.19, P < 0.001 and 2.78 ± 0.14, P < 0.01 × 2.08 ± 0.10, control). Action of F on S3226 (NHE3 inhibitor) sensitive‐component showed NHE3 stimulation (1.18 ± 0.07 × 1.81 ± 0.01, P < 0.0001). MAPK pathway is not involved in this activation, as demonstrated by using U1026 and SB203580 (MEK and p38 MAPK inhibitors), whereas 8 br cAMP (cAMP analogue) and forskolin (phosphodiesterase inhibitor) + IBMX (adenylyl cyclase activator) showed that PKA inhibition plays a role in this response. F stimulated JH+ (mM/min) after an acid pulse in LLC‐PK1, a pig PT cell line (11.44 ± 1.09 3mM F × 5.98 ± 0.82 control, P < 0.01). HOE694 (NHE1 inhibitor) and S3226 showed that F increases NHE3, not NHE1 activity. Signaling pathways investigation showed similar results in PT and LLC‐PK1. Cells were treated or not with F for 5, 15 and 30 min and the ATP and cAMP contents were examined. There was a significant decrease in ATP (47, 53 and 37%, respectively) and in cAMP (45 and 31%, respectively) and a not significant reduction at 30 min. Antibody against phosphorylated substrates showed PKA inhibition in F treated cells. Thus, F stimulates NHE3 activity through PKA inhibition, which increases Na+ reabsorption and can contribute to renal injury.Support: CNPq, FAPESP.
Stimulation of adenosine A1 receptor inhibits the basolateral 50 pS K channels in the thick ascending limb of rat kidney
Authors: li wennan , Wang Lijun , Kong Shumin , Wu Peng , Wang Mingxiao , Luan Haiyan , Gu Li , Fan Lili , Gu Ruimin 
Published: June 2021

We used the patch‐clamp technique to study the effect of stimulation of Adenosine A1 receptor on the basolateral 50 pS K channels in the thick ascending limb (TAL) of rat kidney. 100nM or 200nM Adenosine (ADO) inhibited the basolateral 50 pS K channels. However, 400nM, 800nM and 1μM Adenosine did not decrease the 50 pS K channel activity. Adenosine's effect was mimicked by the specific adenosine A1 receptor agonist Cyclohexyladenosine (CHA). Inhibition of adenosine A1 receptor with 8‐cyclopentyl‐1, 3‐dipropylxanthine (DPCPX), adenosine A1 receptor antagonist, abolished the inhibitory effect of 100nM adenosine. Stimulation of adenosine A1 receptor did not decrease the activity of basolateral 50 pS K channels in the presence of the inhibitor of phospholipase C (PLC), U‐73122 or the inhibitor of protein kinase‐C (PKC), Calphostin‐C, respectively. The mitogen‐activated protein kinase ( MAPK) inhibitors of PD98059 (ERK) or SB202190 (p38) increased the 50 pS K channel activity. PD98059 abolished the inhibitory effect of CHA. CHA decreased the 50 pS K channel activity in the presence of SB202190. These studies show that the inhibitory effect of 100nM adenosine on the basolateral 50 pS K channels, coupled adenosine A1 receptor, is mediated by PLC‐PKC and MAPK (ERK) pathways in the thick ascending limb of the rat kidney.The work is supported by Chinese National Natural Science Foundation 30770800, 31071017 and 31171110.
NADPH oxidase mutation protects against skeletal muscle insulin resistance in high fat fed mice
Authors: Stump Craig S. , Chen Guanjie , Diamond-Stanic Maggie K. , Cantoria Mary Jo , Henriksen Erik J. 
Published: June 2021

In the present study, we hypothesized that NADPH oxidase‐dependent increases in reactive oxygen species (ROS) associated with diet‐induced obesity impair skeletal muscle insulin action and mitochondrial function. Pathogen free B6(Cg)‐Ncf1m1J/J mice ( Jackson Laboratory), which harbor an inactivating mutation for the p47phox subunit of NADPH oxidase, and C57/BL6J (C57) control mice were maintained on either a high fat diet (HF; 45%) or low fat normal chow diet (LF, 10%) for 10 weeks. Final body weights were significantly greater for mice fed HF compared to LF diets in both C57 (29%) and B6(Cg)‐Ncf1m1J/J (30%) mice. Insulin‐stimulated glucose uptake in soleus muscle (ex vivo) was significantly lower in HF vs. LF fed C57 mice (−41%; p<0.05), but not in HF B6(Cg)‐Ncf1m1J/J mice (−6%; p>0.05), suggesting that NADPH oxidase activation is integral to HF diet‐induced muscle insulin resistance. Hindlimb muscle cytochrome oxidase (COX) activity increased with HF feeding in the B6(Cg)‐Ncf1m1J/J mice (38%; p<0.05), but not in HF fed C57 mice. There was no significant change in muscle citrate synthase activity with HF feeding in either the B6(Cg)‐Ncf1m1J/J or C57 mice. In summary, the adverse effects of HF feeding on skeletal muscle insulin sensitivity and mitochondrial COX activity were abrogated in mice with a p47phox subunit inactivating mutation.Supported by an Endocrine Society Research Award.
Treatment with sulodexide, an endothelial glycocalyx‐mimetic, restores glucose tolerance in high fat diet‐fed mice
Authors: Eskens Bart JM , Vink Hans , van Teeffelen Jurgen WGE 
Published: June 2021

We tested if treatment with sulodexide, a glycocalyx‐mimetic, restores glycocalyx dimensions and whole‐body glucose tolerance induced by a high fat diet (HFD) in mice.C57Bl/6 mice were fed normal chow (n=5) or a HFD for 6 weeks (n=16), and half of these HFD‐fed mice were treated with sulodexide in their drinking water (15mg/100mL) for the final two weeks of the feeding period. At the day of experiment, the microcirculation of the hindlimb muscle was measured with a Sidestream Dark‐field camera under anesthesia, and dynamic variations in RBC column width in all visible microvessels were determined. Further, glucose tolerance was measured by i.p. injection of 1g/kg glucose and determining the area under the curve of blood glucose (AUCgluc).While median perfused RBC column diameter (± 6 μm) did not change, HFD mice were associated with increased outward movement of RBCs into glycocalyx (2.5 ± 0.3 μm vs 1.6 ± 0.3 μm in control, P<0.05), and this effect was impaired after sulodexide treatment (2.1 ± 0.3 μm; NS vs control). The AUCgluc was also increased in HFD‐fed mice versus control (1005.2 ± 59.8 mmol/L*90min. vs 773.7.1 ± 55.0 mmol/L*90min, P<0.05) and this effect was prevented after sulodexide treatment (780.4 ± 31.8 mmol/L*90min., NS vs control).In conclusion, two week sulodexide treatment partially restores glycocalyx dimensions and appears to reverse the HFD‐induced decline in whole‐body glucose tolerance in mice.Supported by DFN 2006.00.027, and CTMM work package 01C‐ 104‐04‐PREDICCT
Monocytes Induce Apoptosis of Vascular Smooth Muscle Cells via a Monocyte Chemoattractant Protein‐1 (MCP‐1) Mediated Mechanism
Authors: Wang Qiwei , Morgan Stephanie , Liu Bo 
Published: June 2021

Excessive apoptosis of smooth muscle cells (SMCs) contributes to pathogenesis of abdominal aortic aneurysm (AAA). We have previously demonstrated in a murine model of AAA that apoptotic SMCs stimulate vascular inflammation through production of MCP‐1. In the current study, we tested the hypothesis that MCP‐1 further induces cell death by enhancing the pro‐apoptotic capability of infiltrating inflammatory cells. Cultured mouse aortic SMCs and a mouse monocyte/macrophage cell line RAW264.7 were used. MCP‐1 (100ng/ml, 24h) primed RAWs elicited significant apoptosis of SMCs (2.21±0.349 fold increase in percentage of Annexin V‐PE+/7AAD− cells compared to untreated SMCs, n=5, p<0.05, ANOVA), while untreated RAWs or MCP‐1 had no effect. The pro‐apoptotic effect required cell‐cell contact or proximity between SMCs and RAWs because conditioned media made by MCP‐1 primed RAWs had minimal effect on apoptosis. In a CaCl2 induced murine aneurysm model, co‐staining with TUNEL and MOMA2 showed spatial correlation of apoptosis and monocyte/macrophage in aortic wall 7 days after AAA induction. In conclusion, our results suggest MCP‐1 may play a central role in pathogenesis of AAA. Produced by apoptotic SMCs and other cell types in injured vessels, MCP‐1 contributes directly to the recruitment of inflammatory cells and indirectly to induce apoptosis of SMCs.This work was supported by NIH grant R01HL088447‐01A2 (to B. Liu).
Proteasome inhibition attenuates angiotensin II‐induced hypertension and vascular remodeling
Authors: Li Shuai , Wang Xuejun , Martin Doug 
Published: June 2021

Growing evidence implicates the proteasome in cardiovascular disease. However, its role in hypertension is understudied. Accordingly, this study tested the hypothesis that proteasome inhibition attenuates hypertension development and related vascular remodeling.Male Sprague Dawley rats were given chronic subcutaneous infusion of angiotensin II (AngII) to induce hypertension or vehicle infusion for 2 weeks. The rats were concurrently treated with a proteasome inhibitor, bortezomib (200 μg/kg 3 times per week). Arterial blood pressure was measured from conscious rats via indwelling catheters. After euthanasia the aorta and tibialis anterior skeletal muscle were collected. Histochemical (Masson's Trichrome) and immunohistochemical (CD31) staining were used to estimate wall to lumen ratio and capillary density respectively.Compared to vehicle (131±7 mm Hg), Ang II infusion caused a marked increase in arterial pressure (159±4 mm Hg). Aortic wall to lumen ratio was increased (+20%) whereas capillary density in skeletal muscle was reduced (−30%). Concurrent bortezomib treatment markedly attenuated these responses (arterial pressure 138±5 mm Hg, aorta wall to lumen ratio −1%, capillary density −8%).Collectively, these data suggest that inhibition of the proteasome attenuated Ang II hypertension development and related vascular remodeling. Supported by NIH #2RO1HL63053‐ARRA (DM).
Renal afferent nerve stimulation induces baroreflex resetting through the activation of sympathorenal axis without compromising arterial pressure buffering function
Authors: Tobushi Tomoyuki , Hosokawa Kazuya , Murayama Yoshinori , Saku Keita , Onitsuka Ken , Sakamoto Takafumi , Sakamoto Kazuo , Fujino Takeo , Ikeda Masataka , Kakino Takamori , Ide Tomomi , Sunagawa Kenji 
Published: June 2021

BackgroundChronic kidney disease is known to induce sympathoexcitation, and nephrectomy of those kidneys results in sympathoinhibition. Recent clinical trials indicated that renal nerve ablation markedly suppressed sympathetic nerve activity (SNA). Since the baroreflex system is a powerful regulator of SNA, we examine how renal afferent innervation impacts on baroreflex function to clarify the pathophysiological significance of sympathorenal axis.Methods: In 8 anesthetized rats, we isolated the bilateral carotid sinuses and controlled intra sinus pressure (ISP). We dissected the unilateral renal afferent nerve for electrical stimulation (STM) and measured contralateral splanchnic SNA. We changed ISP from 60 to 180 mmHg stepwise with/without STM and measured arterial pressure (AP) and SNA.Results: STM significantly upward‐shifted the sigmoidal ISP‐SNA relationship (ΔSNA=21.2±2.6%, p<0.01) without changing the maximum gain (1.4±0.8 vs. 1.6±0.8, p=NS) or response range (77.9±16 vs. 95.3±52 mmHg, p=NS). The estimated setpoint pressure increased from 188.7±16.3 to 214.2±13.9 mmHg (p<0.05). STM did not change the SNA‐AP relationship.Conclusion: STM induces baroreflex resetting through the activation of sympathorenal axis. The fact that the baroreflex gain remains unaltered suggests that the renal deafferentiation by ablation lowers AP without compromising AP buffering function.
Roles for Cytosolic NADPH Redox in Regulating Pulmonary Artery Relaxation by Thiol Oxidation‐Elicited Subunit Dimerization of Protein Kinase G 1α
Authors: Neo Boon Hwa , Kandhi Sharath , Wolin Michael S. 
Published: June 2021

The activity of glucose‐6‐phosphate dehydrogenase (G6PD) appears to control a vascular smooth muscle relaxation regulated via cytosolic NADPH oxidation. Since our studies suggest thiol oxidation‐elicited dimerization of protein kinase G 1α (PKG1α) contributes to the relaxation of endothelium‐removed bovine pulmonary arteries (BPA) to H2O2 and responses to hypoxia, we investigated if cytosolic NADPH oxidation promoted relaxation by PKG1α dimerization. Depletion of PKG1α by siRNA inhibited relaxation of BPA to 6‐aminonicotinamide (6‐AN), and attenuated the increase in vasodilator‐stimulated phosphoprotein (VASP) phosphorylation. Relaxation to 6‐AN was not altered by depletion of soluble guanylate cyclase. Depletion of G6PD in BPA with siRNA increased PKG1α dimerization and VASP phosphorylation, and inhibited force generation under hypoxia. Depletion of thioredoxin‐1 and thioredoxin reductase‐1 with siRNA elicited responses similar to G6PD depletion. Thus, cytosolic NADPH redox appears to control relaxation of BPA by PKG1α dimerization through its influence on thioredoxin‐1 redox, and these processes may contribute to vascular responses to hypoxia that are associated with changes in NADPH redox.Supported by NIH grants HL031069, HL043023 and HL066331
EFFECT OF EXOGENOUSLY ADMINISTERED H2S ON THE CARDIAC AND RENAL FUNCTION IN HYPERTENSIVE DIABETIC RATS
Authors: Rathore Hassaan Anwer , Din Fiazud , Abdullah Mohammad H , Khan Ayaz A , Zubaid Munavvar , Abdullah Nor Azizan , Johns Edward J 
Published: June 2021

This study investigated the action of exogenously administered H2S on mean arterial pressure (MAP), heart rate (HR) and renal function in combined states of hypertension and diabetes.Groups (n=6) of spontaneously hypertensive rats (SHR) or DOCA salt hypertensive (DOCA) rats received vehicle, streptozotocin (STZ) or STZ plus Sodium Hydrogen Sulphide (NaHS), at 56μmol/Kg i.p daily for 35 days; theerafter, MAP, HR and GFR were measured in Ketamine + Xylazine anaesthetized rats. Data, mean±SEM, were subjected to ANOVA and significance set at p<0.05.MAP of SHR‐STZ was higher than DOCA‐STZ (145±2 vs 155±2) (p<0.05) whereas it was similar in the SHR‐STZ‐NaHS (132±3 mmHg) and DOCA‐STZ‐NaHS groups. HR of SHR‐STZ at 343±5 b/minwas higher than DOCA‐STZ 314±7b/min (p<0.05) but was similar (312±19b/min) in SHR‐STZ‐NaHS vs DOCA‐STZ‐NaHS. GFR of DOCA‐STZ was lower than SHR‐STZ (0.5±0.03 vs 1.1±0.1ml/min/100g) whereas SHR‐STZ‐NaHS was 66% higher than that of DOCA‐STZ‐NaHS (p<0.05).Improved cardiovascular function with NaHS was likely due to decreased HR and reduced renovascular resistance through vasodilation in both DOCA and SHR concomitant with the development of diabetes.
Palmitic acid activates murine mast cells via Toll like receptor 4 (TLR4)
Authors: Zhang Hanying , Zhao Junxing , Wang Hui , Du Min , Zhu Mei-Jun 
Published: June 2021

Obesity has been closely correlated with aberrant immune status and increasing risk for associated inflammatory diseases. Free fatty acid, which increases in obese condition, is demonstrated to be ligands for Toll like receptor (TLR) 4. Mast cells are critical mediators of innate immunity.ObjectiveTo explore the role of TLR4 in mast cell activation under obese conditions.MethodsP815 mast cells and primary bone marrow mast cells (BMMC) isolated from wild‐type and TLR4 knockout (KO) mice were treated with palmitic acid (PA), and mast cell degranulation, proliferation and associated signaling were analyzed.ResultsPA treatment increased tryptase release and inflammatory cytokine expression in P815 cells; TLR4 inhibitor TAK‐242 blocked this activation but didn't affect their proliferation and apoptosis. Consistently, BMMC separated from TLR4 KO mice failed to be activated by PA despite activation of wild‐type BMMC.ConclusionTLR4 plays important roles in mediating PA induced mast cell activation. Due to the importance of mast cells in inflammation and innate immunity, our data demonstrate that PA induces activation of mast cells via TLR4, which may provide a novel mechanism explaining low‐grade inflammation induced by obesity (RR016474; USDA‐NRI 2008‐35203‐19084; 2009‐65203‐05716).
Regional body volumes in nonobese and obese women and men
Authors: Babb Tony G , Haller Sarah F , Bernhardt Vipa , Locke Kenneth W 
Published: June 2021

Although regional fat distribution is remarkably similar between nonobese and obese women and men, it is unknown whether the compartment volumes are similar between genders or equally increased in obese women and men.We examined abdominal volumes (AVs) in 11 nonobese women (30 yr, 21 BMI), 9 nonobese men (30 yr, 23 BMI), 10 obese women (33 yr, 37 BMI), and 10 obese men (36 yr, 35 BMI). AVs were calculated from whole body MRI and analyzed by independent t‐test with Bonferroni correction (p<0.0125).Subcutaneous (subQ) AV occupied 23±4% and 20±5% of outer AV (p>0.05) in nonobese women and men, respectively, and 53±4% and 37±8% in obese women and men, respectively (p<0.0001). Anterior and posterior subQ AVs did not differ between nonobese women and men (p>0.05); but were greater (p<0.0002) in obese women than obese men. Inner and outer AVs were smaller (p<0.001) in nonobese women than men; while in obese women only inner AV was smaller than in men (p<0.0001). All AVs were greater (p<0.0001) in obese than nonobese women except for inner AV (p>0.0125), and all were greater (p<0.0001) in obese than nonobese men.Thus, despite gender differences in outer and inner AVs, anterior and posterior subQ AVs are similar between nonobese women and men. The increase in AV in obese women is mostly due to an increase in subQ, but not inner AV; while in obese men it is due to increases in both subQ and inner AV.Lithera, Inc, HL096782, King's Fund, ALA, AHA.
Store‐operated calcium channel Orai and STIM regulated by high glucose
Authors: DASKOULIDOU NIKOLETA , Jiang Hongni , Zeng Bo , Atkin Stephen L , Xu Shang-Zhong 
Published: June 2021

The Orai and Stim genes are recently identified as store‐operated calcium channel molecules, which play important roles in essential physiological and pathophysiological functions from gene expression to cell growth. Oxidative stress‐induced endothelial dysfunction is the major etiology for several common diseases, such as hyperglycemia and diabetes. Here we aimed to investigate the expression and function of Orai and Stim and their regulation by high glucose in vascular endothelial cells.The mRNA and protein expression of Orai1–3, STIM1 and STIM2 were detected by real‐time PCR and western blotting in human endothelial cell line EA.hy926 and human blood vessels. Orais and STIMs were upregulated by the chronic treatment with 25 mM high glucose (HG) for 60 hours. The store‐operated Ca2+ influx was enhanced after chronic treatment with HG, however, no effect was observed in the acute experiment with HG perfusion. HG showed no direct effect on Orai1–3 channel activity detected by patch clamp and STIM1 translocation monitored by imaging system in the HEK‐293 cells co‐expressing with Orai and Stim1 genes. The endothelial cell migration and angiogenesis were impaired after HG treatment for 72 hours.Our results suggest the importance of store‐operated channel molecules in the pathophysiology of diabetic blood vessels. This work was supported in part by British Heart Foundation and The Leverhulme Trust.
Annexin A2 acts as scaffolding receptor for plasminogen and tissue plasminogen activator in renal epithelia
Authors: Kaminski Henriette Josephine , Dathe Christin , Neymeyer Hanna , Brand Daniel , Loof Tanja , Peters Harm , Bachmann Sebastian , Paliege Alexander 
Published: June 2021

Annexin A2 has been shown to act as a receptor for plasminogen (Plg) and its tissue type activator (tPA) in endothelial cells (EC). Aim of the present study was to elucidate the renal distribution of the components of this complex under control conditions and in a Thy1 nephritis model of proteinuric renal disease. Thy1 nephritis was induced by intravenous injection of OX7 anti‐Thy1 antibody (1mg/kg body weight). Distribution of Plg, tPA and ANXA2 was studied by immunofluorescence in controls and after 5 or 15 days of OX7 injection. Immunoreactive structures were further characterized by double‐labeling immunofluorescence using antibodies against rat endothelial cell antigen for EC, Na(+),K(+),2Cl(−) cotransporter for thick ascending limbs (TAL), aquaporin‐1 for thin descending limbs (tDL) and aquaporin‐2 for collecting ducts (CD). As expected, all three proteins were identified in EC of controls and Thy1 animals. In addition we found overlapping signal for tPA, Plg and ANXA2 in the basolateral and apical membrane of tDL, TAL and CD both, in treated and untreated animals. Furthermore, abundance of tPA and Plg in the apical membrane of TAL and CD was increased in proteinuric animals. In conclusion, our results provide evidence for the presence of a proteolytic complex in the apical membrane of renal epithelia where it may play a protective role in the setting of proteinuric disease.support: DFG FOR 667