Beneficial effect on podocyte number in experimental diabetic nephropathy resulting from combined atrasentan and RAAS inhibition therapy

2020 ◽  
Vol 318 (5) ◽  
pp. F1295-F1305 ◽  
Author(s):  
Kelly L. Hudkins ◽  
Tomasz A. Wietecha ◽  
Floor Steegh ◽  
Charles E. Alpers
Keyword(s):  
Diabetic Nephropathy ◽  
Underlying Mechanism ◽  
Therapeutic Benefit ◽  
Functional Improvement ◽  
Collagen Type Iv ◽  
Mesangial Matrix ◽  
Similar Treatment ◽  
Type Iv ◽  
Podocyte Loss ◽  
Patients With Diabetes

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.

Investigation of the anti-diabetic nephropathy activity of puerarin

2020 ◽  
Vol 10 (11) ◽  
pp. 1846-1853
Author(s):  
Wen-Feng Zhang ◽  
Yan Yang ◽  
Xin Li ◽  
Bo Yang ◽  
Pei-Yu He ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Collagen Type Iv ◽  
Therapeutic Effects ◽  
Type Iv ◽  
Enzymelinked Immunosorbent Assay ◽  
Hematoxylin And Eosin

Puerarin has potential therapeutic effects on diabetic nephropathy (DN), but the effectiveness as a treatment for DN and the underlying mechanism remain to be elucidated. The DN-like model induced by high glucose in vitro and the DN model induced by streptozotocin in vivo were used to observe the effect of puerarin. The results showed that puerarin can enhance the activity of HBZY-1 cells and reduce apoptosis. in vivo enzymelinked immunosorbent assay and biochemical assay showed that puerarin can improve DN symptoms. Using hematoxylin and eosin staining to stain kidney tissues confirmed that puerarin has a protective effect on DN. Furthermore, puerarin can reduce the content of collagen type IV, laminin LN, tumor necrosis factor, p38, CREB, Fos, Jun, and MMP9 in HBZY-1 cells and DN rats. In conclusion, puerarin can effectively prevent apoptosis in vitro and improve DN-like symptoms by inhibiting the p38/MAPK signaling pathway in vivo. Therefore, puerarin has the potential to treat DN.

Effects of aminoguanidine and vitamin C on collagen type IV in diabetic nephropathy rats

Endocrine ◽  
2010 ◽  
Vol 39 (3) ◽  
pp. 251-258 ◽  
Author(s):  
Qiangxiang Li ◽  
Xiang Ao ◽  
Youhong Du ◽  
Yang Li ◽  
Yangshi Ou ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Vitamin C ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Type Iv

scholarly journals Differential expression of parietal epithelial cell and podocyte extracellular matrix proteins in focal segmental glomerulosclerosis and diabetic nephropathy

2019 ◽  
Vol 317 (6) ◽  
pp. F1680-F1694 ◽  
Author(s):  
Gek Cher Chan ◽  
Diana G. Eng ◽  
Jeffrey H. Miner ◽  
Charles E. Alpers ◽  
Kelly Hudkins ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
Epithelial Cell ◽  
Focal Segmental Glomerulosclerosis ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Type Iv ◽  
Ecm Proteins ◽  
Segmental Glomerulosclerosis ◽  
Parietal Epithelial Cell

In healthy glomeruli, parietal epithelial cell (PEC)-derived extracellular matrix (ECM) proteins include laminin-β1, perlecan, and collagen type IV-α2 and podocyte-specific ECM proteins include laminin-β2, agrin, and collagen type IV-α4. This study aimed to define individual ECM protein isoform expression by PECs in both experimental and human focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) and to determine if changes were CD44 dependent. In experimental FSGS induced with a cytotoxic podocyte antibody and in the BTBR ob/ob mouse model of DN, PEC-derived protein staining was significantly increased in PECs. Dual staining also showed de novo expression of the podocyte-specific ECM proteins laminin-β2 and agrin in PECs. Similar findings were observed in biopsies from patients with FSGS and DN. Increases in individual ECM proteins colocalized with CD44 in PECs in disease. To determine the role of CD44, FSGS was induced in CD44−/− and CD44+/+ mice. PEC staining for perlecan, collagen type IV-α2, laminin-β2, and agrin were significantly lower in diseased CD44−/− mice compared with diseased CD44+/+ mice. These results show that in experimental and human FSGS and DN, PECs typically in an activated state, produce both PEC-derived and podocyte-specific ECM protein isoforms, and that the majority of these changes were dependent on CD44.

scholarly journals Serum anti-collagen type IV IgM antibodies and development of diabetic nephropathy in diabetics with essential hypertension

2016 ◽  
Vol 1 ◽  
pp. 86-92 ◽  
Author(s):  
Asparuh Nikolov ◽  
Ivan Tsinlikov ◽  
Ivanka Tsinlikova ◽  
George Nicoloff ◽  
Alexander Blazhev ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Essential Hypertension ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Igm Antibodies ◽  
Type Iv

Camel milk attenuates the biochemical and morphological features of diabetic nephropathy: Inhibition of Smad1 and collagen type IV synthesis

2015 ◽  
Vol 229 ◽  
pp. 100-108 ◽  
Author(s):  
Aida A. Korish ◽  
Abdel Galil Abdel Gader ◽  
Hesham M. Korashy ◽  
Abdul Majeed Al-Drees ◽  
Abdulqader A. Alhaider ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Collagen Type ◽  
Morphological Features ◽  
Camel Milk ◽  
Collagen Type Iv ◽  
Type Iv

scholarly journals Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling

2020 ◽  
Vol 319 (3) ◽  
pp. F458-F468 ◽  
Author(s):  
Linjing Huang ◽  
Tingting Lin ◽  
Meizhen Shi ◽  
Xiuqing Chen ◽  
Peiwen Wu
Keyword(s):  
Diabetic Nephropathy ◽  
Collagen Type ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Diabetic Rats ◽  
Collagen Type Iv ◽  
Signaling Proteins ◽  
Muscle Actin ◽  
Type Iv

The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg−1·12 h−1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.

THE ROLE OF DETERMINING THE LEVELS OF SERUM COLLAGEN TYPE IV IN DIAGNOSING EARLY DIABETIC NEPHROPATHY

Renal Failure ◽  
2002 ◽  
Vol 24 (6) ◽  
pp. 747-753 ◽  
Author(s):  
Xunhui Xu ◽  
Zhaolong Wu ◽  
Qin Zhou ◽  
Yiwen Zhang ◽  
Dan Wu
Keyword(s):  
Diabetic Nephropathy ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Type Iv ◽  
Serum Collagen ◽  
Early Diabetic Nephropathy

scholarly journals YAP Translocation Precedes Cytoskeletal Rearrangement in Podocyte Stress Response: A Podometric Investigation of Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Kathryn E. Haley ◽  
Mustafa Elshani ◽  
In Hwa Um ◽  
Cameron Bell ◽  
Peter D. Caie ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Underlying Mechanism ◽  
Glomerular Disease ◽  
Automated Image Analysis ◽  
Podocyte Injury ◽  
Cytoskeletal Rearrangement ◽  
Viable Cells ◽  
Podocyte Loss ◽  
Cytoplasmic Translocation ◽  
Grade Iii

Podocyte loss plays a pivotal role in the pathogenesis of glomerular disease. However, the mechanisms underlying podocyte damage and loss remain poorly understood. Although detachment of viable cells has been documented in experimental Diabetic Nephropathy, correlations between reduced podocyte density and disease severity have not yet been established. YAP, a mechanosensing protein, has recently been shown to correlate with glomerular disease progression, however, the underlying mechanism has yet to be fully elucidated. In this study, we sought to document podocyte density in Diabetic Nephropathy using an amended podometric methodology, and to investigate the interplay between YAP and cytoskeletal integrity during podocyte injury. Podocyte density was quantified using TLE4 and GLEPP1 multiplexed immunofluorescence. Fourteen Diabetic Nephropathy cases were analyzed for both podocyte density and cytoplasmic translocation of YAP via automated image analysis. We demonstrate a significant decrease in podocyte density in Grade III/IV cases (124.5 per 106 μm3) relative to Grade I/II cases (226 per 106 μm3) (Student’s t-test, p < 0.001), and further show that YAP translocation precedes cytoskeletal rearrangement following injury. Based on these findings we hypothesize that a significant decrease in podocyte density in late grade Diabetic Nephropathy may be explained by early cytoplasmic translocation of YAP.

scholarly journals ABERRANT N-GLYCOSYLATION REGULATES INVASION OF MG-63 CELLS THROUGH EXTRACELLULAR MATRIX REMODELING

2019 ◽  
pp. 75-79
Author(s):  
SARMILA HANIM MUSTAFA ◽  
MUDIANA MUHAMAD ◽  
SHARANIZA AB-RAHIM
Keyword(s):  
Extracellular Matrix ◽  
Underlying Mechanism ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
High Rate ◽  
Collagen Type Iv ◽  
Matrix Remodeling ◽  
Invasion Rate ◽  
Type Iv ◽  
Qpcr Analysis ◽  
Contrasting Effect

Objective: Despite advances in multimodal therapy, osteosarcoma (OS) still imposes big challenge due to its high rate of metastasis. The previousstudies reported that aberrant glycosylation in the cells mediates the invasion of several cancers including OS. However, its mechanism, particularlyN-glycosylation in OS progression, is still poorly understood. Thus, this study aims to investigate the effect of glycosylation inhibitions toward OS cellsinvasiveness.Materials and Methods: Both 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (1-DMJ) were used to inhibit the activities ofalpha-glucosidase-I/II and alpha-1,2-mannosidase, respectively. Invasion assay and real-time polymerase chain reaction (PCR) (quantitative PCR[qPCR]) analysis of extracellular matrix-related genes were performed at post 24 h of treatment with the inhibitors, 0.5 mM 1-DNJ and 0.5 mM 1-DMJ,respectively, on the OS cell line, MG-63.Results: Results showed that the inhibition of N-glycosylation with 1-DNJ decreases the invasion rate of MG-63 cells while the inhibition ofN-glycosylation by 1-DMJ caused the invasion rate of MG-63 cells to increase. qPCR analysis showed downregulated expression of matrixmetalloproteinase (MMP2) gene in both types of treatments while the expression of its inhibitor, tissue inhibitor of metalloproteinase (TIMP2) wasupregulated in both types of treatments. In this study, MMP9 genes were not detected in both samples; however, the expression of its inhibitor, TIMP1was downregulated in MG-63 cells treated with 1-DNJ but upregulated in 1-DMJ treated cells.Conclusion: It is concluded that 1-DNJ reduced the invasion rate in MG-63 cells through downregulation of MMP2 gene which subsequently reduceddegradation of collagen type IV. However, the contrasting effect showed by 1-DMJ requires further investigation to elucidate its underlying mechanism.

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