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 Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Junghyun Kim ◽  
Eunjin Shon ◽  
Chan-Sik Kim ◽  
Jin Sook Kim
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Glycated Haemoglobin ◽  
Protective Effects ◽  
Podocyte Injury ◽  
Podocyte Loss ◽  
Renal Changes ◽  
Hypoglycemic Drug ◽  
Antioxidant Effects

Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.

scholarly journals Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan

2014 ◽  
Vol 222 (1) ◽  
pp. 43-51 ◽  
Author(s):  
Tetsuhiro Kakimoto ◽  
Kinya Okada ◽  
Yoshihiro Hirohashi ◽  
Raissa Relator ◽  
Mizue Kawai ◽  
...  
Keyword(s):  
Image Analysis ◽  
Diabetic Nephropathy ◽  
Early Stage ◽  
Automated Image Analysis ◽  
Angiotensin Ii Receptor Blocker ◽  
Analysis Method ◽  
Glomerular Injury ◽  
Image Analysis Method ◽  
Podocyte Injury

Diabetic nephropathy is a major complication in diabetes and a leading cause of end-stage renal failure. Glomerular podocytes are functionally and structurally injured early in diabetic nephropathy. A non-obese type 2 diabetes model, the spontaneously diabetic Torii (SDT) rat, is of increasing preclinical interest because of its pathophysiological similarities to human type 2 diabetic complications including diabetic nephropathy. However, podocyte injury in SDT rat glomeruli and the effect of angiotensin II receptor blocker treatment in the early stage have not been reported in detail. Therefore, we have evaluated early stages of glomerular podocyte damage and the beneficial effect of early treatment with losartan in SDT rats using desmin as a sensitive podocyte injury marker. Moreover, we have developed an automated, computational glomerulus recognition method and illustrated its specific application for quantitatively studying glomerular desmin immunoreactivity. This state-of-the-art method enabled automatic recognition and quantification of glomerular desmin-positive areas, eliminating the need to laboriously trace glomerulus borders by hand. The image analysis method not only enabled assessment of a large number of glomeruli, but also clearly demonstrated that glomerular injury was more severe in the juxtamedullary region than in the superficial cortex region. This applied not only in SDT rat diabetic nephropathy but also in puromycin aminonucleoside-induced nephropathy, which was also studied. The proposed glomerulus image analysis method combined with desmin immunohistochemistry should facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetic nephropathy.

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.

scholarly journals Podocytes and Proteinuric Kidney Disease

2015 ◽  
Vol 12 (1) ◽  
pp. 16-19
Author(s):  
Alketa Koroshi ◽  
Alma Idrizi
Keyword(s):  
Treatment Strategies ◽  
Glomerular Disease ◽  
Glomerular Sclerosis ◽  
Endstage Renal Disease ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Glomerular Function ◽  
Podocyte Loss ◽  
Insight Into

Abstract Glomerular disease is the most common cause of endstage renal disease (ESRD), accounting for almost two thirds of cases. In glomerular disease, alterations of po-docytes are of particular importance. Podocyte loss represents a central mediator of glomerular sclerosis. Toxic, genetic, immune, infectious, oxidant, metabolic, hemody-namic, and other mechanisms can all target the podo-cytes. These mechanisms provide new insight into the unique dynamic microenvironment that each individual podocyte inhabits and how it can turn hostile to survival. At the same time, they raise new therapeutic challenges to preserve glomerular function by containing podocyte injury and limiting its spread, both in podo-cytopathies and in other progressive glomerular diseases. Treatment strategies should aim at enhancing podocyte survival. The renin-angiotensin axis blockade, apart from its antifibrotic and intraglomerular hemodynamic effects, has an important role in preventing podocyte loss. However, only long-term observational studies can clarify if many patients will benefit from podocyte-targeted treatment such as abatacept or similar agents.

scholarly journals Long noncoding RNA MEG3 suppresses podocyte injury in diabetic nephropathy by inactivating Wnt/β-catenin signaling

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8016 ◽  
Author(s):  
Xiajing Che ◽  
Xin Deng ◽  
Kewei Xie ◽  
Qin Wang ◽  
Jiayi Yan ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Podocyte Injury ◽  
Migration Assay ◽  
Rna Molecules ◽  
Signaling Activation

Background Diabetic nephropathy (DN) is one of the principal complications of diabetes and podocyte injury plays an important role in the DN pathogenesis. Wnt/β-catenin signaling overactivation confers podocyte injury and promotes multiple types of renal disease. However, the underlying mechanism of Wnt/β-catenin signaling activation in DN progression has not been fully elucidated. Long noncoding RNA (lncRNA) is a large class of endogenous RNA molecules lacking functional code capacity and which participates in the pathogenesis of human disease, including DN. Method A diabetes model was constructed by intraperitoneal injection of Streptozotocin in rats. The MPC5 cells were used to create the in vitro model. Western blot and Quantitative reverse-transcriptase-PCR were used to examine the expression of protein and mRNA. The migrated capacity was analyzed by Transwell migration assay. The cell viability was detected by CCK8. Results In the present study, we revealed the association of lncRNA Maternally Expressed Gene 3 (MEG3) with aberrant activation of Wnt/β-catenin signaling and the role of MEG3/Wnt axis in podocyte injury. We found that high glucose (HG) treatment suppressed MEG3 expression in cultured podocytes, activated Wnt/β-catenin signaling and caused podocyte injury as indicated by the downregulation of podocyte-specific markers (podocin and synaptopodin) and the upregulation of snail1 and α-smooth muscle actin. Overexpression of MEG3 attenuated HG-induced podocyte injury by reducing Wnt/β-catenin activity, repressing cell migration, reactive oxygen species production and increasing the viability of podocytes. Furthermore, we provided evidences that restoration of Wnt/β-catenin signaling by specific agonist impeded the protective effect of MEG3 on podocyte injury. Current results demonstrated that MEG3/Wnt axis plays an important role in fostering podocyte injury and may serve as a potential therapeutic target for the treatment of DN. Conclusion lncRNA MEG3 ameliorates podocyte injury in DN via inactivating Wnt/β-catenin signaling.

Receptor Activator of NF-κB Mediates Podocyte Injury in Diabetic Nephropathy

2021 ◽  
Author(s):  
Guibao Ke ◽  
Xueqin Chen ◽  
Ruyi Liao ◽  
Lixia Xu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Podocyte Injury ◽  
Receptor Activator

scholarly journals Podocytes and the actin cytoskeleton as a feasible therapeutic target

2017 ◽  
Vol 118 (4) ◽  
Author(s):  
Sanja Sever ◽  
Changkyo Gu
Keyword(s):  
Animal Models ◽  
Actin Cytoskeleton ◽  
Therapeutic Target ◽  
Kidney Diseases ◽  
Glomerular Disease ◽  
Podocyte Injury ◽  
Chronic Kidney Diseases ◽  
Beneficial Effects ◽  
Actin Structure

Podocyte injury is a hallmark of the glomerular disease, which is a direct cause of chronic kidney diseases. Importantly, podocyte injury is a consequence of the dysregulation of the actin cytoskeleton. In diverse animal models of proteinuric glomerular disease, recovering the integrity of the actin structure in podocytes resulted in beneficial effects. In this review, we focus on the premise of targeting the actin cytoskeleton as a feasible therapeutics for treating chronic kidney diseases

Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice

2021 ◽  
pp. 096032712110515
Author(s):  
Tianyang Wang ◽  
Xuejiao Wen ◽  
Ziwen Zhang ◽  
Minjuan Xie ◽  
Jie Zhou
Keyword(s):  
Diabetic Nephropathy ◽  
Glycogen Synthase ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Signalling Pathway ◽  
Chinese Herbs ◽  
Diabetic Patients ◽  
Haemoglobin A1c ◽  
Serum Blood Urea Nitrogen ◽  
Gsk 3Β

Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.

scholarly journals Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patricia Q. Rodriguez ◽  
David Unnersjö-Jess ◽  
Sonia S. Zambrano ◽  
Jing Guo ◽  
Katja Möller-Hackbarth ◽  
...  
Keyword(s):  
Critical Role ◽  
Kidney Tissue ◽  
Premature Death ◽  
Glomerular Disease ◽  
Mediator Complex ◽  
Glomerular Diseases ◽  
Vacuole Formation ◽  
Podocyte Loss ◽  
Complex Protein ◽  
Intracellular Vacuole

AbstractPodocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

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