scholarly journals The Pathophysiologic Role of Gelsolin in Chronic Kidney Disease: Focus on Podocytes

2021 ◽  
Vol 22 (24) ◽  
pp. 13281
Author(s):  
Chia-Jung Yu ◽  
Dian W. Damaiyanti ◽  
Shian-Jang Yan ◽  
Chih-Hsing Wu ◽  
Ming-Jer Tang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Critical Role ◽  
Physiological Role ◽  
Small Gtpase ◽  
Common Finding ◽  
Puromycin Aminonucleoside ◽  
Filtration Barrier

Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin cytoskeleton reorganization, resulting in podocyte effacement. Gelsolin plays a critical role in several diseases, including cardiovascular diseases and cancer. Our current study aimed to determine the connection between gelsolin and podocyte, and thus the mechanism underlying podocyte injury in CKD. Experiments were carried out on Drosophila to demonstrate whether gelsolin had a physiological role in maintaining podocyte. Furthermore, the survival rate of gelsolin-knocked down Drosophila larvae was extensively reduced after AgNO3 exposure. Secondly, the in vitro podocytes treated with puromycin aminonucleoside (PAN) enhanced the gelsolin protein expression, as well as small GTPase RhoA and Rac1, which also regulated actin dynamic expression incrementally with the PAN concentrations. Thirdly, we further demonstrated in vivo that GSN was highly expressed inside the glomeruli with mitochondrial dysfunction in a CKD mouse model. Our findings suggest that an excess of gelsolin may contribute to podocytes damage in glomeruli.

scholarly journals A Pilot Study of a Natural Food Supplement as New Possible Therapeutic Approach in Chronic Kidney Disease Patients

2020 ◽  
Vol 13 (7) ◽  
pp. 148 ◽  
Author(s):  
Annalisa Noce ◽  
Alessio Bocedi ◽  
Margherita Campo ◽  
Giulia Marrone ◽  
Manuela Di Lauro ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
High Performance ◽  
Glutathione Transferase ◽  
Food Supplement ◽  
Array Detector ◽  
Natural Food ◽  
Inflammatory Status

The identification of natural bioactive compounds, able to counteract the abnormal increase of oxidative stress and inflammatory status in chronic degenerative non-communicable diseases is useful for the clinical management of these conditions. We tested an oral food supplement (OFS), chemically characterized and evaluated for in vitro and in vivo activity. Vitamin C, analyzed by High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD), was 0.19 mg/g in rosehip dry extract and 15.74 mg/capsule in the OFS. The identification of polyphenols was performed by HPLC-DAD; the total antioxidant capacity was assessed by Folin–Ciocalteu test. Total polyphenols were 14.73 mg/g gallic acid equivalents (GAE) for rosehip extract and 1.93 mg/g GAE for OFS. A total of 21 chronic kidney disease (CKD) patients and 10 healthy volunteers were recruited. The evaluation of routine laboratory and inflammatory parameters, erythrocyte glutathione transferase (e-GST), human oxidized serum albumin (HSAox), and assessment of body composition were performed at two different times, at baseline and after 5 weeks of OFS assumption. In the study, we highlighted a significant decrease of traditional inflammatory biomarkers (such as C-reactive protein, erythrocyte sedimentation rate, platelet to lymphocyte ratio) and other laboratory parameters like e-GST, azotaemia, and albuminuria after OFS treatment in CKD patients. Moreover, we demonstrated a lipid profile improvement in CKD patients after OFS supplementation.

scholarly journals A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action

2011 ◽  
Vol 22 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Xiao-Wei Chen ◽  
Dara Leto ◽  
Tingting Xiong ◽  
Genggeng Yu ◽  
Alan Cheng ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Small Gtpase ◽  
Regulatory Subunit ◽  
Hydrolysis Of ◽  
Identification And Characterization

Insulin stimulates glucose transport in muscle  and adipose tissue by translocation of glucose transporter 4 (GLUT4) to the plasma membrane. We previously reported that activation of the small GTPase RalA downstream of PI 3-kinase plays a critical role in this process by mobilizing the exocyst complex for GLUT4 vesicle targeting in adipocytes. Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. Knockdown of RGC proteins leads to increased RalA activity and glucose uptake in adipocytes. Insulin inhibits the GAP complex through Akt2-catalyzed phosphorylation of RGC2 in vitro and in vivo, while activated Akt relieves the inhibitory effect of RGC proteins on RalA activity. The RGC complex thus connects PI 3-kinase/Akt activity to the transport machineries responsible for GLUT4 translocation.

scholarly journals Mitochondrial Targeting of Herbal Medicine in Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Li ◽  
Changying Xing ◽  
Yanggang Yuan
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Herbal Medicine ◽  
Mitochondrial Function ◽  
Conventional Medicine ◽  
Treatment Options ◽  
Renal Diseases ◽  
Public Health Issue

Chronic kidney disease (CKD) is a common progressive disease that is typically characterized by the permanent loss of nephrons and an eventual decline in glomerular filtration rate. CKD increases mortality and has a significant impact on the quality of life and the economy, which is becoming a major public health issue worldwide. Since current conventional-medicine treatment options for CKD are not satisfactory, many patients seek complementary and alternative medicine treatments including Traditional Chinese Medicine. Herbal medicine is often used to relieve symptoms of renal diseases in the clinic. The kidney is abundant in the number of mitochondria, which provide enough energy for renal function and metabolism. In recent years, a vital role for mitochondrial dysfunction has been suggested in CKD. Mitochondria have become a new target for the treatment of diseases. A growing number of studies have demonstrated herbal medicine could restore mitochondrial function and alleviate renal injury both in vivo and in vitro. In this review, we sum up the therapeutic effect of herbal medicine in CKD via targeting mitochondrial function. This implies future strategies in preventing CKD.

scholarly journals The Function of TIF2/GRIP1 in Mouse Reproduction Is Distinct from Those of SRC-1 and p/CIP

2002 ◽  
Vol 22 (16) ◽  
pp. 5923-5937 ◽  
Author(s):  
Martine Gehin ◽  
Manuel Mark ◽  
Christine Dennefeld ◽  
Andrée Dierich ◽  
Hinrich Gronemeyer ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Stromal Cells ◽  
Critical Role ◽  
Physiological Role ◽  
Mouse Homolog ◽  
Nuclear Receptor Coactivators ◽  
Age Dependent ◽  
Testicular Degeneration

ABSTRACT Human TIF2 (hTIF2) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 and p/CIP. Although the functions of hTIF2 and of its mouse homolog (GRIP1 or mTIF2) have been clearly established in vitro, their physiological role remains elusive. Here, we have generated mice lacking mTIF2/GRIP1 and examined their phenotype with a particular emphasis on reproductive functions. TIF2−/− mice are viable, but the fertility of both sexes is impaired. Male hypofertility is due to defects in both spermiogenesis (teratozoospermia) and age-dependent testicular degeneration, and TIF2 expression appears to be essential for adhesion of Sertoli cells to germ cells. Female hypofertility is due to a placental hypoplasia that most probably reflects a requirement for maternal TIF2 in decidua stromal cells that face the developing placenta. We conclude that TIF2 plays a critical role in mouse reproductive functions, whereas previous reports have not revealed serious fertility impairment in SRC-1−/− or p/CIP−/− mutants. Thus, even though the three p160 coactivators exhibit strong sequence homology and similar activity in assays in vitro, they play distinct physiological roles in vivo, as their genetic eliminations result in distinct pathologies.

scholarly journals Phosphinothricin Acetyltransferases Identified UsingIn Vivo,In Vitro, and Bioinformatic Analyses

2016 ◽  
Vol 82 (24) ◽  
pp. 7041-7051 ◽  
Author(s):  
Chelsey M. VanDrisse ◽  
Kristy L. Hentchel ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Deinococcus Radiodurans ◽  
Phylogenetic Analyses ◽  
Critical Role ◽  
Metabolic Stress ◽  
Physiological Role ◽  
Methionine Sulfoximine ◽  
Acinetobacter Baylyi ◽  
Content Type

ABSTRACTAcetylation of small molecules is widespread in nature, and in some cases, cells use this process to detoxify harmful chemicals.Streptomycesspecies utilize aGcn5N-acetyltransferase (GNAT), known as Bar, to acetylate and detoxify a self-produced toxin,phosphinothricin (PPT), a glutamate analogue. Bar homologues, such as MddA fromSalmonella enterica, acetylate methionine analogues such as methionine sulfoximine (MSX) and methionine sulfone (MSO), but not PPT, even though Bar homologues are annotated as PPT acetyltransferases.S. entericawas used as a heterologous host to determine whether or not putative PPT acetyltransferases from various sources could acetylate PPT, MSX, and MSO.In vitroandin vivoanalyses identified substrates acetylated by putative PPT acetyltransferases fromDeinococcus radiodurans(DR_1057 and DR_1182) andGeobacillus kaustophilus(GK0593 and GK2920).In vivo, synthesis of DR_1182, GK0593, and GK2920 blocked the inhibitory effects of PPT, MSX, and MSO. In contrast, DR_1057 did not detoxify any of the above substrates. Results ofin vitrostudies were consistent with thein vivoresults. In addition, phylogenetic analyses were used to predict the functionality of annotated PPT acetyltransferases inBurkholderia xenovorans,Bacillus subtilis,Staphylococcus aureus,Acinetobacter baylyi, andEscherichia coli.IMPORTANCEThe work reported here provides an example of the use of a heterologous system for the identification of enzyme function. Many members of this superfamily of proteins do not have a known function, or it has been annotated solely on the basis of sequence homology to previously characterized enzymes. The critical role ofGcn5N-acetyltransferases (GNATs) in the modulation of central metabolic processes, and in controlling metabolic stress, necessitates approaches that can reveal their physiological role. The combination ofin vivo,in vitro, and bioinformatics approaches reported here identified GNATs that can acetylate and detoxify phosphinothricin.

scholarly journals Possible Prophylactic Effect of Poria Mushroom Extract on Chemically-Induced Chronic Kidney Disease In Vitro and In Vivo

2019 ◽  
Vol 4 (10) ◽  
Author(s):  
Jonathan Wagmaister ◽  
Kelvin Zheng ◽  
Muhammad Choudhury ◽  
Majid Eshghi ◽  
Sensuke Konno
Keyword(s):  
Chronic Kidney Disease ◽  
Antioxidant Activity ◽  
Kidney Disease ◽  
Cell Viability ◽  
Prophylactic Effect ◽  
Renal Cells ◽  
Mushroom Extract ◽  
Rat Kidneys

Background: Hypothesizing that oxidative stress (OXS) could be a key pathogenic factor for the incidence of chronic kidney disease (CKD), we investigated if the Poria mushroom extract, PE, with possible antioxidant activity, would prevent the incidence of CKD in rats. Materials and Methods: Antioxidant activity of PE was examined against OXS induced by hydrogen peroxide (H2O2) in renal LLC-PK1 cells. Whether PE could prevent the development of CKD in the rat kidneys, mediated through adenine (ADN)-induced OXS, was also examined. After 2 weeks, blood and kidney specimens were collected from rats for blood, histopathologic, and biochemical analyses. Results: Although H2O2-induced OXS led to a significant cell viability reduction in LLC-PK1 cells, PE significantly diminished OXS and sustained high (~70%) cell viability. In rats, ADN-given rats showed typical renal dysfunction with palpable kidney damage; however, PE supplement improved renal function with better histology. A ~2.2-fold increased OXS level was also seen in ADN-given rats but it was reduced by ~27% with PE supplement. Moreover, analysis of kidney injury biomarkers further confirmed extended kidney damage by ADN. Nevertheless, PE effectively maintained the natural status of those markers, protecting the rat kidneys. Conclusions: OXS is indeed harmful to renal cells in vitro and could even lead to ADN-induced CKD in vivo. However, PE appears to have antioxidant activity capable of protecting renal cells and the rat kidneys from such detrimental OXS. Therefore, it is rather possible that PE could be a natural antioxidant with prophylactic effect against OXS-induced CKD.

scholarly journals Quantitative Translation of Microfluidic Transporter in Vitro Data to in Vivo Reveals Impaired Albumin-Facilitated Indoxyl Sulfate Secretion in Chronic Kidney Disease

2019 ◽  
Vol 16 (11) ◽  
pp. 4551-4562 ◽  
Author(s):  
Thomas K. van der Made ◽  
Michele Fedecostante ◽  
Daniel Scotcher ◽  
Amin Rostami-Hodjegan ◽  
Javier Sastre Toraño ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Indoxyl Sulfate ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease

2019 ◽  
Vol 20 (11) ◽  
pp. 2800 ◽  
Author(s):  
Cai-Mei Zheng ◽  
Yung-Ho Hsu ◽  
Chia-Chao Wu ◽  
Chien-Lin Lu ◽  
Wen-Chih Liu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Loss ◽  
Bone Fractures ◽  
Bone Mineralization ◽  
Critical Role ◽  
Beta Catenin ◽  
Mineral Density ◽  
High Turnover

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/β-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.

Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 804-814 ◽  
Author(s):  
Yukihiko Ebisuno ◽  
Koko Katagiri ◽  
Tomoya Katakai ◽  
Yoshihiro Ueda ◽  
Tomomi Nemoto ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Critical Role ◽  
Small Gtpase ◽  
High Endothelial Venules ◽  
Lymphocyte Adhesion ◽  
Peripheral Lymph ◽  
Directional Movement ◽  
Lymphocyte Motility

Abstract The small GTPase Rap1 and its effector RAPL regulate lymphocyte adhesion and motility. However, their precise regulatory roles in the adhesion cascade preceding entry into lymph nodes and during interstitial migration are unclear. Here, we show that Rap1 is indispensably required for the chemokine-triggered initial arrest step of rolling lymphocytes through LFA-1, whereas RAPL is not involved in rapid arrest. RAPL and talin play a critical role in stabilizing lymphocyte arrest to the endothelium of blood vessels under flow or to the high endothelial venules of peripheral lymph nodes in vivo. Further, mutagenesis and peptide studies suggest that release of a trans-acting restraint from the β2 cytoplasmic region of LFA-1 is critical for Rap1-dependent initial arrest. Rap1 or RAPL deficiency severely impaired lymphocyte motility over lymph node stromal cells in vitro, and RAPL deficiency impaired high-velocity directional movement within lymph nodes. These findings reveal the several critical steps of Rap1, which are RAPL-dependent and -independent, in lymphocyte trafficking.

scholarly journals Exogenous Wnt1 Prevents Acute Kidney Injury and Its Subsequent Progression to Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Hong ◽  
Yanni Zhou ◽  
Dedong Wang ◽  
Fuping Lyu ◽  
Tianjun Guan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Blood Biochemical

Studies suggest that Wnt/β-catenin agonists are beneficial in the treatment of acute kidney injury (AKI); however, it remains elusive about its role in the prevention of AKI and its progression to chronic kidney disease (CKD). In this study, renal Wnt/β-catenin signaling was either activated by overexpression of exogenous Wnt1 or inhibited by administration with ICG-001, a small molecule inhibitor of β-catenin signaling, before mice were subjected to ischemia/reperfusion injury (IRI) to induce AKI and subsequent CKD. Our results showed that in vivo expression of exogenous Wnt1 before IR protected mice against AKI, and impeded the progression of AKI to CKD in mice, as evidenced by both blood biochemical and kidney histological analyses. In contrast, pre-treatment of ICG-001 before IR had no effect on renal Wnt/β-catenin signaling or the progression of AKI to CKD. Mechanistically, in vivo expression of exogenous Wnt1 before IR suppressed the expression of proapoptotic proteins in AKI mice, and reduced inflammatory responses in both AKI and CKD mice. Additionally, exogenous Wnt1 inhibited apoptosis of tubular cells induced by hypoxia-reoxygenation (H/R) treatment in vitro. To conclude, the present study provides evidences to support the preventive effect of Wnt/β-catenin activation on IR-related AKI and its subsequent progression to CKD.

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