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Nephron. Experimental Nephrology 2014For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular... (Review)
Review
BACKGROUND
For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular injury and even glomerulosclerosis can undergo regression under certain circumstances. The problem with glomerular regeneration is centered around the podocyte, a highly specialized cell that is the critical constituent of the glomerular filtration barrier.
SUMMARY
Podocytes are characterized by a complex cytoskeleton that makes them unable to proliferate. Thus, once their depletion reaches a specific threshold, it is considered to be irreversible. The discovery of cells with the aptitude to differentiate into podocytes in the adult kidney, i.e. renal progenitor cells (RPCs), was a critical step in understanding the mechanisms of glomerular repair. Accumulating evidence suggests that a tight regulation of many different signaling pathways, such as Notch, Wnt, and microRNA, is involved in a correct regenerative process and that an altered regulation of these same signaling pathways in RPCs triggers the generation of focal segmental glomerulosclerosis lesions. In particular, regeneration is severely impaired by proteinuria, when albumin sequesters retinoic acid and blocks RPC differentiation in podocytes.
KEY MESSAGES
RPC maintenance and differentiating potential are regulated by complex mechanisms that can be implemented following glomerular injury and can be manipulated to activate regeneration for therapeutic purposes. A better understanding of the phenomenon of glomerular regeneration paves the way for the prevention and treatment of glomerular diseases.
Topics: Animals; Cell Differentiation; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Glomerulus; Podocytes; Regeneration; Signal Transduction; Stem Cells
PubMed: 24854644
DOI: 10.1159/000360669 -
Scientific Reports Nov 2023The renal glomerulus represents the major filtration body of the vertebrate nephron and is responsible for urine production and a number of other functions such as...
The renal glomerulus represents the major filtration body of the vertebrate nephron and is responsible for urine production and a number of other functions such as metabolic waste elimination and the regulation of water, electrolyte and acid-base balance. Podocytes are highly specialized epithelial cells that form a crucial part of the glomerular filtration barrier (GFB) by establishing a slit diaphragm for semipermeable plasma ultrafiltration. Defects of the GFB lead to proteinuria and impaired kidney function often resulting in end-stage renal failure. Although significant knowledge has been acquired in recent years, many aspects in podocyte biology are still incompletely understood. By using zebrafish as a vertebrate in vivo model, we report a novel role of the Kinesin-like motor protein Kif21a in glomerular filtration. Our studies demonstrate specific Kif21a localization to the podocytes. Its deficiency resulted in altered podocyte morphology leading to podocyte foot process effacement and altered slit diaphragm formation. Finally, we proved considerable functional consequences of Kif21a deficiency by demonstrating a leaky GFB resulting in severe proteinuria. Conclusively, our data identified a novel role of Kif21a for proper GFB function and adds another piece to the understanding of podocyte architecture and regulation.
Topics: Animals; Glomerular Filtration Barrier; Kidney Glomerulus; Podocytes; Proteinuria; Zebrafish; Kinesins; Zebrafish Proteins
PubMed: 37932480
DOI: 10.1038/s41598-023-46270-1 -
Physiology (Bethesda, Md.) Apr 2005The kidneys filter the plasma in special filtration units-glomeruli-and thereby excrete low-molecular-weight waste products into the urine. The mechanisms of glomerular... (Review)
Review
The kidneys filter the plasma in special filtration units-glomeruli-and thereby excrete low-molecular-weight waste products into the urine. The mechanisms of glomerular filtration have been a matter of controversy for several decades, but recent data have revealed new details about the molecular nature of the filter and have demonstrated a central role for the podocyte slit diaphragm in the filtration process.
Topics: Animals; Humans; Kidney Glomerulus; Plasma; Proteinuria; Ultrafiltration
PubMed: 15772298
DOI: 10.1152/physiol.00045.2004 -
American Journal of Physiology. Renal... Oct 2023Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their... (Review)
Review
Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can contribute to loss of glomerular filtration function. This review provides a comprehensive update of current understanding of the regulation and biogenesis of fenestrae. We consider diseases in which GEnC fenestration loss is recognized or may play a role and discuss methods with potential to facilitate the study of these critical structures. Literature is drawn from GEnCs as well as other fenestrated cell types such as liver sinusoidal endothelial cells that most closely parallel GEnCs.
Topics: Humans; Endothelial Cells; Endothelium; Kidney Glomerulus; Glomerular Filtration Barrier; Kidney Diseases
PubMed: 37471420
DOI: 10.1152/ajprenal.00036.2023 -
Physiological Reports Sep 2020A novel anatomically accurate model of rat glomerular filtration is used to quantify shear stresses on the glomerular capillary endothelium and hoop stresses on the...
A novel anatomically accurate model of rat glomerular filtration is used to quantify shear stresses on the glomerular capillary endothelium and hoop stresses on the glomerular capillary walls. Plasma, erythrocyte volume, and plasma protein mass are distributed at network nodes using pressure differentials calculated taking into account volume loss to filtration, improving on previous models which only took into account blood apparent viscosity in calculating pressures throughout the network. Filtration is found to be heterogeneously distributed throughout the glomerular capillary network and is determined by concentration of plasma proteins and surface area of the filtering capillary segments. Hoop stress is primarily concentrated near the afferent arteriole, whereas shear stress is concentrated near the efferent arteriole. Using parameters from glomerular micropuncture studies, conditions of diabetes mellitus (DM), 5/6-Nephrectomy (5/6-Nx), and Angiotensin II-induced hypertension (HTN) are simulated and compared to their own internal controls to assess the changes in mechanical stresses. Hoop stress is increased in all three conditions, while shear stress is increased in 5/6-Nx, decreased in HTN, and maintained at control levels in DM by the hypertrophic response of the glomerular capillaries. The results indicate that these alterations in mechanical stresses and the consequent release of cytokines by or injury of the glomerular cells may play a significant role in the progression of glomerulopathy in these disease conditions.
Topics: Animals; Diabetic Nephropathies; Hemodynamics; Hypertension, Renal; Kidney Glomerulus; Models, Theoretical; Rats; Stress, Mechanical
PubMed: 32951361
DOI: 10.14814/phy2.14577 -
Journal of the American Society of... Oct 2015Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is...
Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference-mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm-mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm-mediated signaling to preserve glomerular function and podocyte viability in adult mice.
Topics: Age Factors; Animals; Cell Survival; Kidney Glomerulus; Male; Membrane Proteins; Mice; Mice, Transgenic; Podocytes
PubMed: 25644109
DOI: 10.1681/ASN.2014040405 -
Kidney International. Supplement Aug 2007Glomerular visceral epithelial cells, namely podocytes, are highly specialized cells and give rise to primary processes, secondary processes, and finally foot processes.... (Review)
Review
Glomerular visceral epithelial cells, namely podocytes, are highly specialized cells and give rise to primary processes, secondary processes, and finally foot processes. The foot processes of neighboring podocytes interdigitate, leaving between them filtration slits. These are bridged by an extracellular substance, known as the slit diaphragm, which plays a major role in establishing size-selective barrier to protein loss. Furthermore, podocytes are known to synthesize matrix molecules to the glomerular basement membrane (GBM), including type IV collagen, laminin, entactin, and agrin. Because diabetic nephropathy is clinically characterized by proteinuria and pathologically by glomerular hypertrophy and GBM thickening with foot process effacement, podocytes have been the focus in the field of research on diabetic nephropathy. As a result, many investigations have demonstrated that the diabetic milieu per se, hemodynamic changes, and local growth factors such as transforming growth factor-beta and angiotensin II, which are considered mediators in the pathogenesis of diabetic nephropathy, induce directly and/or indirectly hypertrophy, apoptosis, and structural changes, and increase type IV collagen synthesis in podocytes. This review explores some of the structural and functional changes of podocytes under diabetic conditions and their role in the development and progression of diabetic nephropathy.
Topics: Cell Proliferation; Diabetic Nephropathies; Disease Progression; Humans; Hypertrophy; Intercellular Junctions; Kidney Glomerulus; Podocytes
PubMed: 17653209
DOI: 10.1038/sj.ki.5002384 -
American Journal of Physiology. Renal... Oct 2001Recent progress in relating the functional properties of the glomerular capillary wall to its unique structure is reviewed. The fenestrated endothelium, glomerular... (Review)
Review
Recent progress in relating the functional properties of the glomerular capillary wall to its unique structure is reviewed. The fenestrated endothelium, glomerular basement membrane (GBM), and epithelial filtration slits form a series arrangement in which the flow diverges as it enters the GBM from the fenestrae and converges again at the filtration slits. A hydrodynamic model that combines morphometric findings with water flow data in isolated GBM has predicted overall hydraulic permeabilities that are consistent with measurements in vivo. The resistance of the GBM to water flow, which accounts for roughly half that of the capillary wall, is strongly dependent on the extent to which the GBM surfaces are blocked by cells. The spatial frequency of filtration slits is predicted to be a very important determinant of the overall hydraulic permeability, in keeping with observations in several glomerular diseases in humans. Whereas the hydraulic resistances of the cell layers and GBM are additive, the overall sieving coefficient for a macromolecule (its concentration in Bowman's space divided by that in plasma) is the product of the sieving coefficients for the individual layers. Models for macromolecule filtration reveal that the individual sieving coefficients are influenced by one another and by the filtrate velocity, requiring great care in extrapolating in vitro observations to the living animal. The size selectivity of the glomerular capillary has been shown to be determined largely by the cellular layers, rather than the GBM. Controversial findings concerning glomerular charge selectivity are reviewed, and it is concluded that there is good evidence for a role of charge in restricting the transmural movement of albumin. Also discussed is an effect of albumin that has received little attention, namely, its tendency to increase the sieving coefficients of test macromolecules via steric interactions. Among the unresolved issues are the specific contributions of the endothelial glycocalyx and epithelial slit diaphragm to the overall hydraulic resistance and macromolecule selectivity and the nanostructural basis for the observed permeability properties of the GBM.
Topics: Animals; Capillary Permeability; Humans; Kidney Glomerulus; Models, Biological; Ultrafiltration
PubMed: 11553505
DOI: 10.1152/ajprenal.2001.281.4.F579 -
Physiological Reviews Jan 2003Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits... (Review)
Review
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.
Topics: Animals; Basement Membrane; Cell Cycle; Cytoskeleton; Gene Expression; Humans; Kidney Glomerulus
PubMed: 12506131
DOI: 10.1152/physrev.00020.2002 -
Organogenesis 2011The glomerular basement membrane (GBM) is a crucial component of the kidney's filtration barrier that separates the vasculature from the urinary space. During... (Review)
Review
The glomerular basement membrane (GBM) is a crucial component of the kidney's filtration barrier that separates the vasculature from the urinary space. During glomerulogenesis, the GBM is formed from fusion of two distinct basement membranes, one synthesized by the glomerular epithelial cell (podocyte) and the other by the glomerular endothelial cell. The main components of the GBM are laminin-521 (α5β2γ1), collagen α3α4α5(IV), nidogen and the heparan sulfate proteoglycan, agrin. By studying mice lacking specific GBM components, we have shown that during glomerulogenesis, laminin is the only one that is required for GBM integrity and in turn, the GBM is required for completion of glomerulogenesis and glomerular vascularization. In addition, our results from laminin β2-null mice suggest that laminin-521, and thus the GBM, contribute to the establishment and maintenance of the glomerular filtration barrier to plasma albumin. In contrast, mutations that affect GBM collagen IV or agrin do not impair glomerular development or cause immediate leakage of plasma proteins. However, collagen IV mutation, which causes Alport syndrome and ESRD in humans, leads to gradual damage to the GBM that eventually leads to albuminuria and renal failure. These results highlight the importance of the GBM for establishing and maintaining a perfectly functioning, highly selective glomerular filter.
Topics: Animals; Glomerular Basement Membrane; Heparan Sulfate Proteoglycans; Humans; Kidney Glomerulus; Laminin; Organogenesis; Permeability
PubMed: 21519194
DOI: 10.4161/org.7.2.15275