bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ameliorated Glomerular Injury in Mice Overexpressing Brain Natriuretic Peptide with Renal Ablation
Authors: KASAHARA MASATO , MUKOYAMA MASASHI , SUGAWARA AKIRA , MAKINO HISASHI , SUGANAMI TAKAYOSHI , OGAWA YOSHIHIRO , NAKAGAWA MASAYO , YAHATA KENSEI , GOTO MASAHISA , ISHIBASHI RIEKO , TAMURA NAOHISA , TANAKA ISSEI , NAKAO KAZUWA 
Published: April 2021

Abstract.
Brain natriuretic peptide (BNP) is a cardiac hormone produced by the ventricle, and its secretion is markedly increased in heart failure, hypertension, and renal failure. Transgenic mice that overexpress BNP in the liver (BNP-Tg) were recently generated, resulting in low BP. To elucidate the role of BNP in renal pathophysiology, the effect of chronic excess of BNP in transgenic mice on glomerular injury after subtotal nephrectomy induced by resection of the renal poles was examined. After nephrectomy, glomerular cross-sectional areas in control nontransgenic mice markedly increased as compared with those in sham-operated mice (+81 ± 7%), whereas there was only a modest increase in BNP-Tg (+10 ± 6%). Expansion of the mesangial area and increase in the intraglomerular cell number were also inhibited in BNP-Tg. Glomerular expressions of transforming growth factor-β and fibronectin were increased with hypertrophy and were significantly suppressed in BNP-Tg. Furthermore, increases in the urinary albumin excretion and BP were significantly ameliorated in BNP-Tg. Chronic hydralazine treatment in nephrectomized nontransgenic mice failed to inhibit glomerular hypertrophy. These findings indicate that the chronic excess of BNP in mice ameliorates glomerular hypertrophy and mesangial expansion after renal ablation. The results also suggest that the observed effects of natriuretic peptides under reduced renal mass are not due merely to systemic BP reduction and may be therapeutically applicable in various renal diseases.
Endothelin A Receptor Blockade Prevents Capillary/Myocyte Mismatch in the Heart of Uremic Animals
Authors: AMANN KERSTIN , MÜNTER KLAUS , WESSELS SABINE , WAGNER JÜRGEN , BALAJEW VITALI , HERGENRÖDER STEFAN , MALL GERHARD , RITZ EBERHARD 
Published: April 2021

Abstract.
In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ETA-receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ETA-receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription—PCR. Changes in cardiac ETA-and ETB-PCR. receptor mRNA were measured using reverse transcription—PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 ± 535 mm/mm3) was found compared with sham-operated controls (3995 ± 471 mm/mm3); this was also seen in animals that were treated with trandolapril (3503 ± 533 mm/mm3) but not in animals that were treated with LU 135252 (3800 ± 303 mm/mm3). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.
Comparative Effects of Cerivastatin and Fenofibrate on the Atherogenic Lipoprotein Phenotype in Proteinuric Renal Disease
Authors: DEIGHAN CHRISTOPHER J. , CASLAKE MURIEL J. , MCCONNELL MICHAEL , BOULTON-JONES J. MICHAEL , PACKARD CHRISTOPHER J. 
Published: April 2021

Abstract.
Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P < 0.01), triglyceride (14%, P < 0.05), LDL cholesterol (LDL-C; 23%, P < 0.01), total LDL (18%, P < 0.01), and LDLIII concentration (27% P < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r2 = 34%, P < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P < 0.01). HDL-C (19%, P < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r2 = 67%, P < 0.001; RLP cholesterol r2 = 58%, P < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 ± 85 mg/dl after cerivastatin treatment and 133 ± 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.
Clinical and Genetic Evaluation of Familial Steroid-Responsive Nephrotic Syndrome in Childhood
Authors: FUCHSHUBER ARNO , GRIBOUVAL OLIVIER , RONNER VERA , KROISS SABINE , KARLE STEPHANIE , BRANDIS MATTHIAS , HILDEBRANDT FRIEDHELM 
Published: April 2021

Abstract.
Steroid-responsive idiopathic nephrotic syndrome (SSINS) is the most common form of nephrotic syndrome in childhood. This article reports a cohort of familial SSINS with disease onset in childhood. The clinical course in terms of age at onset, symptoms during the initial phase, renal morphology, and outcome was evaluated. Furthermore, linkage to NPHS2, the gene for autosomal-recessive steroid-resistant INS on chromosome 1, was examined. Two families with haplotypes consistent with linkage to NPHS2 were evaluated for mutations in the NPHS2 gene. Familial SSINS (32 patients from 15 families, minimal change NS in 12 of 12 biopsies) was found to be a clinically homogeneous entity. Interfamilial and intrafamilial variability with respect to the age at disease onset was low, indicating a strong genetic influence on disease onset. By linkage studies and mutational analysis, familial SSINS was found to be genetically distinct from NPHS2. This is the first report of a large cohort of familial SSINS. Exclusion of linkage to NPHS2 makes likely the existence of a distinct gene locus for SSINS.
Podocytes Respond to Mechanical Stress In Vitro
Authors: ENDLICH NICOLE , KRESS KAI R. , REISER JOCHEN , UTTENWEILER DIETMAR , KRIZ WILHELM , MUNDEL PETER , ENDLICH KARLHANS 
Published: April 2021

Abstract.
Glomerular capillary pressure is thought to affect the structure and function of glomerular cells. However, it is unknown whether podocytes are intrinsically sensitive to mechanical forces. In the present study, differentiated mouse podocytes were cultured on flexible silicone membranes. Biaxial cyclic stress (0.5 Hz and 5% linear strain) was applied to the membranes for up to 3 d. Mechanical stress reduced the size of podocyte cell bodies, and processes became thin and elongated. Podocytes did not align in the inhomogeneous force field. Whereas the network of microtubules and that of the intermediate filament vimentin exhibited no major changes, mechanical stress induced a reversible reorganization of the actin cytoskeleton: transversal stress fibers (SF) disappeared and radial SF that were connected to an actin-rich center (ARC) formed. Epithelial and fibroblast cell lines did not exhibit a comparable stress-induced reorganization of the F-actin. Confocal and electron microscopy revealed an ellipsoidal and dense filamentous structure of the ARC. Myosin II, α-actinin, and the podocyte-specific protein synaptopodin were present in radial SF, but, opposite to F-actin, they were not enriched in the ARC. The formation of the ARC and of radial SF in response to mechanical stress was inhibited by nonspecific blockade of Ca2+ influx with Ni2+ (1 mM), by Rho kinase inhibition with Y-27632 (10 μM), but not by inhibition of stretch-activated cation channels with Gd3+ (50 μM). In summary, mechanical stress induces a unique reorganization of the actin cytoskeleton in podocytes, featuring radial SF and an ARC, which differ in protein composition. The F-actin reorganization in response to mechanical stress depends on Ca2+ influx and Rho kinase. The present study provides the first direct evidence that podocytes are mechanosensitive.
Upregulation of the Secretory-Type Na+/K+/2Cl--Cotransporter in the Kidney by Metabolic Acidosis and Dehydration in Rats
Authors: IKEBE MIKA , NONOGUCHI HIROSHI , NAKAYAMA YUSHI , TASHIMA YUKA , TOMITA KIMIO 
Published: April 2021

Abstract.
The functional role and mechanisms of regulation of the Na+/K+/2Cl--cotransporter NKCC1 in the kidney have not yet been clarified. NKCC1 mRNA and protein expression in control rats, rats with dehydration (2 d), and rats with metabolic acidosis (NH4Cl in the food for 6 to 7 d) was examined using reverse transcription-PCR and Western blotting. In contrast to the abundant NKCC1 mRNA expression in the terminal inner medullary collecting ducts in mice, expression was found to be most abundant in the outer medullary collecting ducts (OMCD) in rats. Dehydration and metabolic acidosis increased NKCC1 mRNA expression three- to fivefold not only in the OMCD but also in the cortical collecting ducts and inner medullary collecting ducts. Dehydration and metabolic acidosis increased NKCC1 protein expression twofold in the membrane fraction from the outer medulla. NKCC1 protein expression was observed not in the microdissected medullary thick ascending limbs but in the OMCD, and it was stimulated twofold by dehydration and metabolic acidosis. Incubation of OMCD in low-pH medium increased NKCC1 mRNA expression. In summary, NKCC1 mRNA and protein expression is upregulated with dehydration and metabolic acidosis. NKCC1 may play an important role in adaptation to these physiologic conditions. Low pH and possibly hypertonicity stimulate NKCC1 mRNA expression in OMCD.
Expression of Angiotensinogen mRNA and Protein in Angiotensin II-Dependent Hypertension
Authors: KOBORI HIROYUKI , HARRISON-BERNARD LISA M. , NAVAR L. GABRIEL 
Published: April 2021

Abstract.
Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 ± 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 ± 1 mmHg). Plasma renin activity was markedly suppressed (0.2 ± 0.1 versus 5.3 ± 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 ± 29 versus 99 ± 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52- or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/control value ratios of 3.79 ± 1.16 versus 1.00 ± 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with shamtreated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 ± 0.11 versus 0.58 ± 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 ± 0.07 versus 1.32 ± 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngII-generating capacity that paradoxically occurs in AngII-treated hypertensive rats.
Characterization and Signaling of the AT4 Receptor in Human Proximal Tubule Epithelial (HK-2) Cells
Authors: HANDA RAJASH K. 
Published: April 2021

Abstract.

125I-divalinal-angiotensin IV (metabolically resistant analog of angiotensin IV) was used as a receptor ligand to identify the expression and properties of the angiotensin AT4 receptor in epithelial HK-2 cells (an immortalized cell line derived from adult human proximal tubules). Saturation binding isotherms revealed that HK-2 cells contain a saturable 125I-divalinal-angiotensin IV binding site with an affinity of 3 nmol/L and a density of 508 fmol/mg protein. An analysis of ligand specificity showed that only angiotensin AT4 receptor ligands (angiotensin IV and divalinal-angiotensin IV) competed with both a high- and low-affinity binding site. GTPγS and dithiothreitol did not affect 125I-Ang IV or 125I-divalinal-Ang IV binding, suggesting that the AT4 receptor was not G-protein coupled and did not require sulfhydryl bonds for receptor affinity. Activation of the AT4 receptor caused a complex concentration-dependent rise in [Ca2+]i, an elevation in [Na+]i, and increased mitogen-activated protein kinase activity. These results suggest that human proximal tubule epithelial cells contain functional AT4 receptors that are pharmacologically similar to the AT4 receptor described in more distal segments of the nephron. Furthermore, the AT4 receptor uses several intracellular signaling pathways to convey information.
Prognostic Value of Angiotensin-I Converting Enzyme I/D Polymorphism for Nephropathy in Type 1 Diabetes Mellitus
Authors: HADJADJ SAMY , BELLOUM RIADH , BOUHANICK BÉATRICE , GALLOIS YVES , GUILLOTEAU GÉRARD , CHATELLIER GILLES , ALHENC-GELAS FRANC[COMBINING CEDILLA]OIS , MARRE MICHEL 
Published: April 2021

Abstract.
Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine ≥ 150 μmol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 ± 231 versus 466 ± 181 μg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.
Suppression of Constitutive but Not IL-1β-Inducible Expression of Monocyte Chemoattractant Protein-1 in Mesangial Cells by Retinoic Acids
Authors: LUCIO-CAZANA JAVIER , NAKAYAMA KENJI , XU QIHE , KONTA TSUNEO , MORENO-MANZANO VICTORIA , FURUSU AKIRA , KITAMURA MASANORI 
Published: April 2021

Abstract.
Retinoic acid regulates a wide range of biologic processes, including inflammation. This study investigated the effect of all-trans-retinoic acid (t-RA) on the constitutive and cytokine-inducible expression of monocyte chemoattractant protein 1 (MCP-1) in rat mesangial cells. Serum-deprived mesangial cells exhibited substantial levels of MCP-1 mRNA, and the expression was markedly upregulated by interleukin-1β (IL-1β). Pretreatment with t-RA abrogated the constitutive mRNA expression but did not inhibit the IL-1β-inducible expression. The similar effects were observed by 9-cis-RA. The suppressive effect of t-RA required retinoic acid receptors. t-RA did not affect the stability of MCP-1 mRNA, indicating that its suppressive effect was at the transcriptional level. Experiments that used pharmacologic and genetic inhibitors showed that the IL-1β-inducible MCP-1 expression was dependent on nuclear factor-κB (NF-κB) and independent of activator protein 1 (AP-1). In contrast, the constitutive expression of MCP-1 was dependent on both NF-κB and AP-1. t-RA substantially inhibited the constitutive activity of AP-1 but did not inhibit NF-κB activity in mesangial cells. These data suggested that (1) constitutive and IL-1β-inducible expression of MCP-1 was differently regulated by AP-1 and NF-κB and (2) t-RA inhibited selectively the constitutive expression of MCP-1 via intervention in the AP-1 pathway.
CD40 Is Expressed on Human Peritoneal Mesothelial Cells and Upregulates the Production of Interleukin-15 and RANTES
Authors: BASOK ANNA , SHNAIDER ALLA , MAN LIMOR , CHAIMOVITZ CIDIO , DOUVDEVANI AMOS 
Published: April 2021

Abstract.
Limited data are available concerning the interaction between lymphocytes and human peritoneal mesothelial cells (HPMC) during peritonitis. CD40 is a member of the tumor necrosis factor (TNF) family of receptors whose ligand (CD154) is mainly expressed on the membrane of activated CD4-positive lymphocytes. CD154-CD40 cross-linking is a central event in antigen presentation, B-cell activation by T cells, and regulation of cytokine secretion from various types of cells. The goal of this study was to demonstrate in vitro the presence of CD40 on HPMC and to test its functionality in inducing interleukin-15 (IL-15) and RANTES. We assayed the levels of CD40 by reverse transcription-PCR and flow cytometry and IL-15 and RANTES by enzyme-linked immunosorbent assay. Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40. HPMC express CD40 mRNA and protein. After stimulation with interferon-γ (IFNγ, 5U/ml) or TNFα (1 ng/ml), there was a small increase in CD40 mRNA and protein levels; when both cytokines were applied, the increase in CD40 levels was more than threefold. CD40 ligation induced IL-15 production by HPMC and was additive to IFNγ stimulation. CD40 ligation was strongly synergistic with IFNγ in induction of RANTES (20-fold as compared with unstimulated HPMC), whereas neither ligation nor IFNγ alone could induce RANTES. Pretreatment of HPMC with TNFα and IFNγ increased the response to CD40 ligation in magnitudes that correlated with the elevation of CD40 levels induced by the pretreatment. To conclude, the presence of a functional CD40 on HPMC whose ligation induced IL-15 and RANTES production was detected. It is possible that this receptor acts as a major mediator of T-cell—regulated immune and inflammatory response during peritonitis.
Thrombospondin-1 Is the Key Activator of TGF-β1 in Human Mesangial Cells Exposed to High Glucose
Authors: YEVDOKIMOVA NATALIA , WAHAB NADIA ABDEL , MASON ROGER M. 
Published: April 2021

Abstract.
Elevated levels of transforming growth factor-β1 (TGF-β1) are synthesized by human mesangial cells that are cultured in medium that contains high concentrations of glucose and mediate increased synthesis of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), and changes in the expression of other genes. TGF-β1 is synthesized as a latent complex. Previous work indicated that high-glucose conditions also upregulate expression of thrombospondin-1 (TSP-1), a potential activator of latent TGF-β1. With the use of the synthetic peptide GGWSHW, an inhibitor of the TSP-1 activation mechanism, endogenous TSP-1 is shown to be responsible for converting high levels of latent TGF-β1 to bioactive growth factor over 3 wk of exposure of mesangial cells to 30 mM D-glucose. Peptide inhibition of TGF-β1 activation by TSP-1 in high-glucose conditions completely suppressed increases in FN and PAI-1 expression. Treating mesangial cells maintained in high glucose with a TSP-1 antisense oligonucleotide reduced TSP-1 expression to levels found in 4 mM D-glucose cultures, prevented TGF-β1 activation, and normalized expression of FN.