scholarly journals The cell biology of renal filtration

2015 ◽  
Vol 209 (2) ◽  
pp. 199-210 ◽  
Author(s):  
Rizaldy P. Scott ◽  
Susan E. Quaggin
Keyword(s):  
Cell Biology ◽  
Molecular Size ◽  
Renal Glomerulus ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Glomerular Function ◽  
Selective Filter ◽  
Circulating Cells ◽  
Filtration Barrier ◽  
Glomerular Capillaries

The function of the kidney, filtering blood and concentrating metabolic waste into urine, takes place in an intricate and functionally elegant structure called the renal glomerulus. Normal glomerular function retains circulating cells and valuable macromolecular components of plasma in blood, resulting in urine with just trace amounts of proteins. Endothelial cells of glomerular capillaries, the podocytes wrapped around them, and the fused extracellular matrix these cells form altogether comprise the glomerular filtration barrier, a dynamic and highly selective filter that sieves on the basis of molecular size and electrical charge. Current understanding of the structural organization and the cellular and molecular basis of renal filtration draws from studies of human glomerular diseases and animal models of glomerular dysfunction.

Cell Biology of the Glomerular Podocyte

2003 ◽  
Vol 83 (1) ◽  
pp. 253-307 ◽  
Author(s):  
Hermann Pavenstädt ◽  
Wilhelm Kriz ◽  
Matthias Kretzler
Keyword(s):  
Glomerular Filtration ◽  
Cell Biology ◽  
Considerable Increase ◽  
Gene Products ◽  
Common Theme ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Selective Permeability ◽  
Filtration Barrier

Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

scholarly journals Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

2016 ◽  
Vol 40 (5) ◽  
pp. 819-830 ◽  
Author(s):  
Janina Müller-Deile ◽  
Finn Gellrich ◽  
Heiko Schenk ◽  
Patricia Schroder ◽  
Jenny Nyström ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Glomerular Filtration ◽  
Cell Types ◽  
Endothelial Damage ◽  
Micro Rna ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Glomerular Endothelial Cells ◽  
Apoptotic Pathways

Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

Permeability of Peritoneal and Glomerular Capillaries: What are the Differences According to Pore Theory?

2011 ◽  
Vol 31 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Bengt Rippe ◽  
Simon Davies
Keyword(s):  
Glomerular Filtration ◽  
Matrix Theory ◽  
Complex Structure ◽  
Gel Filtration ◽  
Diffusion Path ◽  
Peritoneal Membrane ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Shed Light ◽  
Glomerular Capillaries

Pore and fiber-matrix theory can both be used to model the peritoneal and glomerular filtration barriers in an attempt to shed light on their differing structure–function relationships. The glomerular filtration barrier (GFB) is structurally more specialized, morphologically complex, and also highly dynamic; but paradoxically, because of its uniformity, it conforms more closely to the predictions of pore theory than does the peritoneum, and it in fact resembles a more simple synthetic membrane. Compared with the peritoneal capillary wall, the GFB has no transcellular “third” pores (aquaporins), and it is far less leaky and more size-selective to proteins, mainly as a result of having far fewer “large” pores. It does have charge-selective properties, although these are considered much less important in excluding albumin than was once thought, and it is also able to select polymers according to their shape and flexibility. Even this property might reflect the relative uniformity of the GFB, which has a high diffusion area and short diffusion distances, compared with the peritoneal barrier, which behaves more like a gel filtration column. Furthermore, the length of the diffusion path across the peritoneal membrane is much greater for small solutes, given the relatively high ultrafiltration coefficient for that membrane compared with the GFB—a situation that reflects both the tortuosity of the interendothelial clefts and the distribution of peritoneal capillaries within the interstitium. These comparisons reveal the peritoneal barrier as a relatively complex structure to model; and yet this model may be more representative of the general microcirculation, and thus shed light on systemic endothelial function in renal failure.

scholarly journals Understanding the Mechanisms of Proteinuria: Therapeutic Implications

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Jorge E. Toblli ◽  
P. Bevione ◽  
F. Di Gennaro ◽  
L. Madalena ◽  
G. Cao ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Strong Predictor ◽  
Large Body ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Wide Range

A large body of evidence indicates that proteinuria is a strong predictor of morbidity, a cause of inflammation, oxidative stress and progression of chronic kidney disease, and development of cardiovascular disease. The processes that lead to proteinuria are complex and involve factors such as glomerular hemodynamic, tubular absorption, and diffusion gradients. Alterations in various different molecular pathways and interactions may lead to the identical clinical end points of proteinuria and chronic kidney disease. Glomerular diseases include a wide range of immune and nonimmune insults that may target and thus damage some components of the glomerular filtration barrier. In many of these conditions, the renal visceral epithelial cell (podocyte) responds to injury along defined pathways, which may explain the resultant clinical and histological changes. The recent discovery of the molecular components of the slit diaphragm, specialized structure of podocyte-podocyte interaction, has been a major breakthrough in understanding the crucial role of the epithelial layer of the glomerular barrier and the pathogenesis of proteinuria. Thispaper provides an overview and update on the structure and function of the glomerular filtration barrier and the pathogenesis of proteinuria, highlighting the role of the podocyte in this setting. In addition, current antiproteinuric therapeutic approaches are briefly commented.

scholarly journals A Review of Podocyte Biology

2018 ◽  
Vol 47 (Suppl. 1) ◽  
pp. 3-13 ◽  
Author(s):  
Puneet Garg
Keyword(s):  
Minimal Change Disease ◽  
Intercellular Junctions ◽  
Minimal Change ◽  
Glomerular Sclerosis ◽  
Renal Glomerulus ◽  
Detailed Structure ◽  
Filtration Barrier ◽  
Potential Applications ◽  
Foot Process ◽  
Glomerular Capillaries

Background: Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement. Summary: Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting.

Roles of the podocyte in glomerular function

2000 ◽  
Vol 278 (2) ◽  
pp. F173-F179 ◽  
Author(s):  
Hermann Pavenstädt
Keyword(s):  
Cell Culture ◽  
Cellular Response ◽  
Cell Type ◽  
Cellular Functions ◽  
Glomerular Diseases ◽  
Glomerular Function ◽  
Cell Culture Techniques ◽  
Culture Techniques ◽  
Filtration Barrier ◽  
Crucial Component

The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that podocyte foot processes counteract the elastic force of the glomerular basement membrane and that vasoactive hormones may regulate the contractile state of their foot processes and thereby modulate the ultrafiltration coefficient K f. Podocyte damage leads to proteinuria, and podocyte injury occurs in many glomerular diseases, which may progress to chronic renal failure. The understanding of the regulation of physiological properties of the podocyte and the mechanisms of its cellular response to injury may thus provide a clue to the understanding of the pathogenesis of proteinuria and glomerular diseases. In the past it was difficult to study cellular functions in this cell type, because of its unique anatomic location and the difficulty in characterizing podocytes in cell culture. However, recent advances in physiological, molecular biological, and cell culture techniques have increased the knowledge of the role of the podocyte in glomerular function. The present review attempts to outline new aspects of podocyte function in the glomerulum.

scholarly journals Podocyte Autophagy in Homeostasis and Disease

2021 ◽  
Vol 10 (6) ◽  
pp. 1184
Author(s):  
Qisheng Lin ◽  
Khadija Banu ◽  
Zhaohui Ni ◽  
Jeremy S. Leventhal ◽  
Madhav C. Menon
Keyword(s):  
Glomerular Filtration ◽  
Functional Role ◽  
Specific Reference ◽  
Protective Mechanism ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Cellular Autophagy ◽  
Survival Mechanisms

Autophagy is a protective mechanism that removes dysfunctional components and provides nutrition for cells. Podocytes are terminally differentiated specialized epithelial cells that wrap around the capillaries of the glomerular filtration barrier and show high autophagy level at the baseline. Here, we provide an overview of cellular autophagy and its regulation in homeostasis with specific reference to podocytes. We discuss recent data that have focused on the functional role and regulation of autophagy during podocyte injury in experimental and clinical glomerular diseases. A thorough understanding of podocyte autophagy could shed novel insights into podocyte survival mechanisms with injury and offer potential targets for novel therapeutics for glomerular disease.

scholarly journals The TRPC6-AMPK pathway is involved in cytoskeleton reorganization and glucose uptake in podocytes

2018 ◽  
Author(s):  
Patrycja Rachubik ◽  
Maria Szrejder ◽  
Dorota Rogacka ◽  
Irena Audzeyenka ◽  
Michał Rychłowski ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glomerular Filtration ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Cytoskeleton Reorganization ◽  
Insulin Dependent ◽  
Trpc6 Channel ◽  
Amp Activated Protein Kinase ◽  
Glomerular Capillaries

AbstractPodocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes and are involved in regulating glomerular filtration barrier. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. Insulin regulates the interaction of TRPC6 with AMPKα2 in cultured rat podocytes The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKα2, actin cytoskeleton reorganization and glucose uptake in podocyte. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes.

scholarly journals A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 149
Author(s):  
Nina Sopel ◽  
Alexandra Ohs ◽  
Mario Schiffer ◽  
Janina Müller-Deile
Keyword(s):  
Intracellular Signaling ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Fine Tuning ◽  
Extracellular Matrix Protein ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Canonical Pathways

Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways.

The balance of autocrine VEGF-A and VEGF-C determines podocyte survival

2009 ◽  
Vol 297 (6) ◽  
pp. F1656-F1667 ◽  
Author(s):  
Janina Müller-Deile ◽  
Kirstin Worthmann ◽  
Moin Saleem ◽  
Irini Tossidou ◽  
Hermann Haller ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Vascular Endothelial ◽  
Direct Effects ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Glomerular Endothelium ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

Podocytes are an important component of the glomerular filtration barrier and are the major source of vascular endothelial growth factor (VEGF) in the glomerulus. The role of VEGF for the phenotype of the glomerular endothelium has been intensely studied; however, the direct effects of autocrine VEGF on the podocyte are largely unknown. In this study we characterized the expression of VEGF isoforms and VEGF receptors in cultured human podocytes and examined direct effects on cell signaling and apoptosis after stimulation with exogenous VEGF or ablation of autocrine VEGF. We identified VEGF-A and VEGF-C as the dominant isoforms in human podocytes and showed that autocrine levels of both are important for the intracellular activation of antiapoptotic phosphoinositol 3-kinase/AKT and suppression of the proapoptotic p38MAPK via VEGFR-2. We demonstrated that ablation of VEGF-A or VEGF-C as well as treatment with bevacizumab or a VEGFR-2/-3 tyrosine kinase inhibitor led to reduced podocyte survival. In contrast, ablation of VEGF-B had no effect on podocyte survival. Treatment with exogenous VEGF-C reversed the effect of VEGF-A neutralization, and exogenous VEGF-A abrogated the effect of VEGF-C ablation in human podocytes. Our results underline the importance of autocrine VEGF for podocyte survival and indicate the delicate balance of VEGF-A and VEGF-C to influence progression of glomerular diseases.

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