Version May 2024
INTRODUCTION — The healthy kidney filters water-soluble, non-protein-bound metabolic byproducts into the urine but prevents the passage of albumin and other larger essential molecules. This selective filtration occurs across the glomerular capillary wall:
●Under normal circumstances, the glomerular capillary wall is extremely permeable to water and small solutes but negligibly to albumin or other proteins of equivalent or larger molecular weight.
●Defects in the glomerular capillary wall result in increased permeability to albumin and proteins of similar or even larger size, causing proteinuria.
●Electrical potential differences generated by transglomerular flow may modulate the flux of anionic (charged) albumin across the glomerular capillary wall [1].
The traditional view that the glomerular capillary wall hinders the transit of protein is largely based upon micropuncture studies that demonstrated very low concentrations of albumin in Bowman's space in non-nephrotic animals [2,3]. This view has been challenged by newer data that have demonstrated by intravital 2-photon microscopy, much higher concentrations of albumin in Bowman's space than were reported previously [4]. Given the novelty of the technique of intravital multiphoton microscopy (MPM), these observations need to be validated in other systems and species, especially since they substantially alter our understanding of the pathogenesis of proteinuria [5-8].
It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). It has been hypothesized that proteins cross the GBM mainly by diffusion rather than by liquid flow, whereas water crosses entirely by flow [9]. Alternatively, generation of a filtration-dependent electric potential difference could influence the glomerular sieving coefficient of albumin [1]. Several factors may prevent clogging of the filter with large proteins. An active transport involving the neonatal Fc receptor has been identified that may remove immunoglobulins that accumulate at the filtration barrier [10]. In addition, human podocytes perform polarized, caveolae-dependent albumin endocytosis [11] and also undergo macropinocytosis at sites of membrane ruffling (a clathrin-independent specialized endocytic process defined by the formation of large vesicles measuring 0.2 to 5 microm in diameter). Free fatty acids associated with serum albumin stimulate macropinocytosis, which may amplify the effect of proteinuria in the nephrotic syndrome [12]. All of these clearance processes may coexist to avoid clogging of the glomerular filter. Genetic or acquired impairment of the clearance machinery may be a common mechanism promoting glomerular diseases.
Over the last decade, studies among patients with hereditary proteinuric syndromes have markedly advanced our knowledge of the structure and composition of the glomerular capillary wall and the changes in its composition that lead to proteinuria. However, the changes in the glomerular capillary wall that underlie proteinuria in hereditary diseases do not necessarily account for the proteinuria that accompanies acquired causes of nephrotic syndrome, which are much more common. Thus, the underlying molecular mechanisms of acquired proteinuric diseases remain less well characterized.
It is increasingly appreciated that defects in podocyte structure and function result in increased glomerular permeability. This topic review will focus primarily on the biology of glomerular podocytes and defects in podocyte structure that appear to underlie many proteinuric kidney diseases.
Reviews of clinical proteinuria, including causes, manifestations, and treatment of specific glomerular disease, are presented separately:
●(See "Overview of heavy proteinuria and the nephrotic syndrome".)
●(See "Evaluation of proteinuria in children".)
●(See "Glomerular disease: Evaluation and differential diagnosis in adults".)
●(See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)
GLOMERULAR CAPILLARY WALL — To better appreciate the biology of glomerular podocytes, it is important to understand the structural and functional anatomy of the glomerular capillary wall.
The glomerular capillary wall, through which the filtrate must pass, consists of the following three layers:
●Fenestrated capillary endothelium, extensively coated with a layer of polyanionic glycosaminoglycans and glycoproteins.
●Glomerular basement membrane (GBM), containing laminin-521, collagen alpha3 alpha4 alpha5 (IV), nidogen, and the heparan sulfate proteoglycan, entactin.
●Podocytes (or epithelial cells), which are attached to the GBM by discrete foot processes. The pores between the foot processes (slit pores) are closed by a thin membrane called the slit diaphragm, which functions as a modified adherens junction and may also be permeated by anatomical pores [13].
Defects in any of the three components of the glomerular capillary wall can lead to proteinuria (picture 1) [14-17]. In addition, crosstalk between podocytes and endothelial and mesangial cells are key to the maintenance of glomerular capillary wall function. As examples, the production of vascular endothelial growth factor (VEGF) by podocytes is necessary for the integrity of the glomerular endothelium [18], and the upregulation and secretion of the podocyte protein, angiopoietin-like-4 (Angptl4) into the glomerular capillary wall causes marked proteinuria in experimental models of nephrotic syndrome [19]. Multiphoton microscopy (MPM) has the necessary spatial and temporal resolution to study complex cell-to-cell interactions between different cell types of the glomerular filtration barrier as well as circulating blood cells and plasma factors in vivo [8].
PODOCYTES — Podocytes are terminally differentiated epithelial cells that have large cell bodies and long primary or major processes. The primary processes attach to the underlying glomerular basement membrane (GBM) via multiple foot processes. Adhesion molecules, such as alpha3beta1 integrin complex and dystroglycan (which are present on the basal membrane of foot processes), attach the podocyte to the GBM [20].
Slit diaphragm — The interdigitating foot processes of adjacent podocytes are joined laterally by slit diaphragms that bridge the intervening filtration slits. The following proteins have been found to comprise the slit diaphragm, which should be considered as a unique category of intercellular junction [21]:
●Nephrin [22]
●Neph1 and neph2 [23-26]
●FAT1 and FAT2 [27]
●Podocin [28]
●Transient receptor potential cation channel 6 (TRPC6) [29,30]
●Tight junction proteins, including junctional adhesion molecule A, cingulin, and the huge scaffold protein ZO-1 [31,32]
Slit diaphragms are complex signalling hubs that execute highly specialized functions. They interact with the actin cytoskeleton of podocyte foot processes via linker proteins. These include CD2-associated protein (CD2AP) [33-35], Nck [36,37], zona occludens-1, and the catenins. Selective deletion of Nck expression in podocytes of adult mice leads to proteinuria, glomerulosclerosis, and altered morphology of foot processes [38]. Mutations of some of the genes that encode slit diaphragm proteins cause rearrangement of the actin cytoskeleton, which results in foot process effacement and proteinuria [38]. The use of phosphoproteomics has identified 146 phosphorylation sites on proteins abundantly expressed in podocytes, and as one example, phosphorylation occurs at a site on the podocin protein that is mutated in a genetic form of nephrotic syndrome [39].
Nephrin and neph1 also interact directly with the Par3-aPKC protein complex at the podocyte intercellular junction, suggesting that this complex plays a key role in the establishment and maintenance of podocyte polarity as it does in other polarized epithelia and neurons [40-42].
A discussion of the evidence showing that abnormalities of these proteins are causative in some congenital disorders and that autoantibodies targeting nephrin are associated with minimal change disease is presented separately:
●(See "Congenital nephrotic syndrome".)
●(See "Focal segmental glomerulosclerosis: Genetic causes".)
Actin cytoskeleton — Podocyte architecture is maintained by a contractile apparatus composed of microfilaments comprising actin, type I and type II myosins, alpha-actinin, talin, paxillin, vinculin, and palladin [43,44]. The opposing effects of molecules such as slit-1-Robo2 and cofilin-1, which counteract filament polymerization, are equally important to the actin cytoskeleton. This cytoskeleton helps to support the glomerular capillary wall, which is subject to the high hydrostatic pressure necessary for glomerular filtration and plays a key role in the foot process architecture (figure 1). The actin cytoskeleton also contributes to the highly motile character of these specialized cells. Mutations in known regulators of the actin cytoskeleton have been implicated in the etiology of proteinuric diseases.
Immunofluorescence and confocal microscopy have demonstrated two distinct actin cytoskeletal networks present in the foot processes [45]:
●Dense actin bundles are present above the level of the slit diaphragm and extend parallel to the longitudinal axis (figure 2).
●A cortical actin network extends just below the plasma membrane of the foot processes.
Different actin-binding proteins are associated with each of these networks. Thus, whereas alpha-actinin and synaptopodin are associated with the actin bundles above the slit diaphragm, the cortical actin network colocalizes with cortactin [45].
Endocytosis, mitochondrial fitness, and autophagy — The concept that podocytes internalize and remove proteins was proposed over 50 years ago. However, the physiological relevance of this has remained elusive, although some studies noted a requirement for endocytic processes in podocytes [46,47]. As an example, podocyte deficiency in the vacuolar protein sorting-34 (Vps34), which controls several vesicular trafficking processes, leads to podocyte vacuolization and defective autophagy, early proteinuria, glomerular scarring, and death [48]. Rat and human podocytes in culture display the two endocytic receptors, megalin and cubilin, which are responsible for the only documented process for protein reabsorption in proximal tubule cells [47,49]. Defective lysosomal activity, as observed in mice deficient in the lysosomal proteinase cathepsin-D, induces apoptotic podocyte death followed by proteinuria and glomerulosclerosis [50].
Mitochondrial health is important for podocyte function and for providing protection from apoptosis [51]. Mitochondria are dynamic organelles that periodically divide (fission) and fuse (fusion). Mitochondrial fission is closely associated with key features of diabetic nephropathy [52]. Podocyte deficiency in dynamin-related protein 1 (Drp1), a protein which is essential for mitochondrial fission, improves mitochondrial fitness and protects against progression of diabetic nephropathy [53]. Some mitochondrial disorders of the podocyte could be amenable to treatment-targeted approaches. As an example, rapamycin has extended the lifespan of mice deficient in the mitochondrial membrane protein prohibitin-2 (PHB2), which develop disorganized mitochondria and missing cristae, foot process effacement, glomerulosclerosis, albuminuria, and kidney function impairment [54].
In addition to endocytosis and mitochondrial fitness, autophagy has been identified as a major pathway that delivers damaged proteins and organelles to lysosomes in order to maintain cellular homeostasis. Autophagy is substantially increased in glomeruli from mice with induced proteinuria and from patients with acquired proteinuric diseases. Podocyte-specific deletion of autophagy-related-5 (Atg5) led to a glomerulopathy in aging mice and strongly increased susceptibility to models of glomerular disease [55]. When Atg5 or Atg7 were mutated during nephrogenesis, mice developed a disease similar to focal segmental glomerulosclerosis (FSGS) [56]. Analogous changes were observed in human idiopathic FSGS kidney biopsy specimens. Podocytes from patients with minimal change disease (MCD) have higher levels of Beclin-1-mediated autophagic activity than glomeruli from FSGS patients. Also, repeat kidney biopsies confirmed that patients maintaining high podocyte autophagic activity retained MCD status, whereas patients with decreased podocyte autophagic activity progressed to FSGS [57]. Impaired autophagy resulting in mitochondrial dysfunction and endoplasmic reticulum stress could play a major role in the progression of podocytopathies.
Foot process effacement and cytoskeleton rearrangement — Flattening of foot processes or foot process effacement is a characteristic histologic finding associated with most primary and secondary glomerular diseases. It could represent a protective response of podocytes to escape detachment from the GBM [58,59]. Rearrangement of the actin cytoskeleton is necessary for foot process effacement to occur, and stabilization of the actin cytoskeleton decreases proteinuria. The actin cytoskeleton is a fluid structure that can be quickly and reversibly reorganized. Experimental evidence suggests it is a direct target of cyclosporine A, which is an effective treatment for reducing nephrotic-range proteinuria among patients with MCD [60]. The effect of cyclosporine A on the cytoskeleton appears to be independent of its effect on T cell dysfunction [60].
Other therapies used to treat patients with nephrotic syndrome have also been found to have direct effects on podocyte function distinct from their immunosuppressive effects. As examples:
●In one study, treatment of cultured podocytes with glucocorticoids (dexamethasone) stabilized the podocyte actin cytoskeleton, protecting against and enhancing recovery from puromycin aminonucleoside (PAN)-induced podocyte injury [61].
●Rituximab may also have a podocyte effect through stabilization of acid sphingomyelinase (ASM)-like phosphodiesterase 3b, which regulates the generation of ceramide [62]. This mechanism is proposed to stabilize the actin cytoskeleton.
●Synthetic adrenocorticotropic hormone (ACTH) has been shown to reduce proteinuria and improve glomerular filtration rate (GFR) in patients with membranous nephropathy and other nephrotic syndromes resistant to standard immunosuppressive therapy [63-65]. The benefits of ACTH appear to be mediated by its direct effect on the melanocortin 1 receptor (MCR1) expressed by podocytes [66,67] and not through stimulation of glucocorticoid secretion.
Actin is normally organized into coordinated stress fibers in mature foot processes. Podocyte injury causes the rearrangement of actin to a dense network [20].
The cytoskeleton can be altered by at least four different mechanisms:
●Direct injury of podocytes can occur by systemic or locally produced toxins (ie, reactive oxygen species [ROS]), viral infection, drugs (pamidronate, interferon), or local activation of the renin-angiotensin system (RAS) [68]. (See "Focal segmental glomerulosclerosis: Pathogenesis".)
●Abnormalities of cytoskeletal structural proteins can adversely affect cytoskeletal dynamics. An example is mutations of alpha-actinin-4, which cause hereditary FSGS [69]. This abnormality increases the affinity of alpha-actinin-4 for actin, which may alter cytoskeletal fluidity. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'ACTN4 gene'.)
The disruption of myosin 1e in mice promotes podocyte injury with foot process effacement [70]. Genetic variations in the MYH9 locus were associated with progressive nondiabetic proteinuric kidney disease in individuals of recent African ancestry [71,72], although subsequent analysis showed the causative genetic variants lie in the APOL1 gene that resides on the same chromosome [73]. APOL1 encodes an apolipoprotein expressed at high levels in the liver and lower levels in podocytes, endothelial cells, and immune cells. A number of putative mechanisms for podocyte injury in patients carrying APOL1 risk alleles have been proposed including cationic pore-forming ability, altered autophagy, and direct toxicity [74-76]. The drug inaxaplin, which inhibits cationic influx stimulated by APOL1, reduces proteinuria in patients with FSGS and APOL1 high-risk variants [77]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients' and "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Investigational therapies'.)
●Injury to the slit diaphragm, arising from congenital or acquired disorders (such as drug toxicity or viral infection), can initiate abnormal actin and nephrin signaling, resulting in cytoskeletal reorganization [14,20-22,25,26,78].
●Changes in the structure of the GBM may lead to cytoskeletal derangements, such as in laminin beta 2-deficient mice, in which proteinuria precedes foot process effacement [79], and in mice with the HANAC syndrome Col4a1 mutation that develop proteinuria at birth [80].
The mechanism by which podocyte injury or mutations in genes for slit diaphragm proteins initiate rearrangement of the cytoskeleton is unclear. Similar intracellular events, such as phosphorylation of constituent proteins, appear to occur during development of the foot processes and after podocyte injury. During podocyte differentiation, for example, nephrin is transiently phosphorylated on multiple tyrosine residues by the Src family kinase, Fyn [36]. Phosphorylation of nephrin allows its interaction with Nck, which is required for actin reorganization [81]. Decreased nephrin phosphorylation may occur following podocyte injury [36-38]. Nephrin tyrosine phosphorylation is required to stabilize and restore podocyte foot process architecture, and a model has been presented in which changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton [82].
Another possible mechanism of cytoskeletal rearrangement is via the degradation of dynamin, a GTPase protein that is generally considered to have a key role in deforming cellular membranes. Dynamin associates with actin, possibly via the actin-binding protein, cortactin [83,84].
Cleavage of dynamin by cathepsin-L may initiate reorganization of the cytoskeleton, resulting in clinical disease. Support for this is provided by findings in animal models and some human glomerular diseases (figure 3) [85,86]:
●Levels of cathepsin-L were found to be increased in a murine model of MCD [85]. This increase has also been observed in patients with membranous nephropathy, FSGS, and diabetic nephropathy, although significant increases were not found in those with other proteinuric kidney diseases [86].
●Proteinuria and foot process effacement induced by lipopolysaccharide are abrogated in cathepsin-L-knockout mice [85].
●Whereas the expression of a cathepsin-L-degraded dynamin fragment causes foot process effacement and proteinuria, the expression of cathepsin-L-resistant dynamin mutants decreases proteinuria.
Cytoskeletal rearrangement may also be induced by the urokinase receptor (uPAR) via its activation of the vitronectin receptor, alphavbeta3 integrin [87]. The absence of uPAR, beta3 integrin, or the alphavbeta3 integrin ligand, vitronectin, protects mice from developing lipopolysaccharide-induced proteinuria. This protection is abolished by exogenous expression of either uPAR or a constitutively active beta3 integrin in mice [87]. The uPAR may be required to activate alphavbeta3 integrin in podocytes promoting cell motility and activation of small GTPases.
Direct podocyte injury — Podocytes may be direct targets of injury in acquired proteinuric diseases [88]. Injury may be immunologic or nonimmunologic. An example of an immunologic cause of podocyte injury is the effect of antibodies directed to the phospholipase A2 receptor (PLA2R) in primary membranous nephropathy. This effect is mediated by complement activation leading to the formation of the membrane attack complex and possibly also by interfering with the receptor function [89]. Circulating factors may also lead to severe, recurrent podocyte injury that is reversible [90]. Autoantibodies to the slit diaphragm protein nephrin have been reported in patients with minimal change disease [91].
●(See "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'.)
Nonimmunologic causes of podocyte injury include viral infection (specifically, HIV), drug toxicity (eg, pamidronate), local activation of the RAS, and ROS.
HIV nephropathy is characterized by collapsing FSGS. (See "HIV-associated nephropathy (HIVAN)".)
A number of case reports have documented collapsing glomerulopathy, podocytopathy, and tubulopathy in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [92-97]. Similar to HIV-associated nephropathy (HIVAN), there appears to be an increased risk of collapsing FSGS and podocytopathy in patients carrying high-kidney-risk genetic variants in the APOL1 gene [73]. Existing models suggest that increased intrinsic expression of APOL1 within podocytes is necessary for glomerular injury and interferon leads to increased expression of APOL1 [98], which is present in patients with coronavirus disease 2019 (COVID-19). Intriguingly, collapsing FSGS occurred in the allograft of a transplant recipient infected with SARS-CoV-2; however, the donor APOL1 genotype was determined to be low risk and the recipient's APOL1 genotype was high risk (G1/G2), suggesting that extrarenal expression of APOL1 high-risk variants may be pathogenic [92].
Clinical studies and animal models have shown that the podocyte is directly infected by HIV genes and may provide a reservoir for replicating virus [99,100]. Exogenous expression of HIV genes, Nef and Vpr, causes dedifferentiation, proliferation and loss of contact inhibition, and apoptosis of podocytes [99-106]. It is not yet clear whether SARS-CoV-2 virus is directly toxic to the podocyte, although identification of virus in podocytes has been reported in kidney biopsies from patients [107-109]. Furthermore, podocytes have been reported to express all components required for SARS-CoV-2 entry including the ACE2 receptor, the TRPMSS2 protease, and furin [110,111]. Finally, some believe that parvo B19 virus may have similar toxic effects as HIV on podocyte [88].
Inhibition of systemic RAS limits the progression of chronic kidney disease in the setting of proteinuria [112]. This is due, in part, to a reduction of transglomerular pressure. However, locally produced angiotensin may also have direct toxic effects on the podocyte. Angiotensin receptor-1 and -2 are expressed by podocytes [113]. Mechanical strain of cultured podocytes increases expression of the angiotensin receptor-1 as well as angiotensin-II and enhances podocyte apoptosis, which is abrogated by angiotensin receptor blockade [68]. Furthermore, a transgenic rat that overexpresses the angiotensin receptor-1, specifically in podocytes, is characterized by proteinuria and structural changes in the podocyte that include effacement and detachment [114]. The prorenin receptor is highly expressed on podocytes and promotes podocyte function and survival by maintaining autophagy and protein turnover machinery. It also contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity [115].
ROS are produced in a number of conditions including PAN nephrosis [116], complement activation, and metabolic disorders such as obesity. In patients with obesity that are prone to develop FSGS, albuminuria is negatively correlated with plasma adiponectin, while adiponectin knockout mice exhibit albuminuria and effacement of podocyte foot processes. The protective effect of adiponectin seems to occur through activation of adiponectin receptors expressed on the podocyte membrane and reduction of oxidative stress [117].
A number of signaling pathways may lead to podocyte injury and proteinuria:
●In human proteinuric kidney diseases such as diabetic nephropathy and FSGS, upregulation of Wnt1 and active beta-catenin is observed in podocytes, while podocyte-specific knockout of beta-catenin protects against development of albuminuria [118].
●Podocytes possess the complete machinery for glutamatergic signaling, and derangements in that signaling may lead to proteinuric kidney diseases [119].
●The Notch pathway seems to be involved in the development of proteinuria because Notch intracellular domain is detected in injured podocytes and genetic inactivation or pharmacologic inhibition of Notch ameliorates proteinuria and podocyte damage [120,121].
●AKT2, a member of the AKT family of serine/threonine kinases that regulate adaptation to many cellular stress-induced processes, has an essential role in podocyte protection after nephron reduction. This protein triggers a compensatory mechanism that involves mouse double minute-2 homolog (Mdm2), glycogen synthase kinase-3 (Gsk3), and Rac1. AKT2 activation by mammalian (mechanistic) target of rapamycin complex-2 (mTORC2) is also required for podocyte survival in human chronic kidney disease. These data provide an explanation for the adverse kidney effect of sirolimus and a criterion for the rational use of this drug [122].
●Calcium/calmodulin-dependent protein kinase IV (CaMK4) is a serine-threonine kinase that regulates multiple aspects of the immune response. In rodent models of lupus nephritis and non-immune podocytopathies, expression of CaMK4 is increased [123]. Targeted inhibition of CaMK4 in podocytes is protective, reversing effects of increased CaMK4 on Rac1-mediated podocyte motility and phosphorylation of the scaffold protein 14-3-3, which leads to degradation of synaptopodin [123].
Programmed cell death protein 1 (PD-1) surface receptor and its two ligands (PD-L1 and PD-L2) are increased in podocytes isolated from aged mice, and PDCD1 transcript is increased with age in microdissected human glomeruli. Administration of anti-PD-1 antibody increased the life span of podocytes and improved podocyte number and lowered proteinuria in young mice with FSGS [124].
Podocyte-specific deletion of Dicer, an enzyme that generates microRNA (small, noncoding RNA that function as important regulators of gene expression) alters cytoskeletal dynamics and induces proteinuria and glomerulosclerosis [123,125,126].
Podocyte depletion — A decrease in podocyte number resulting from apoptosis or detachment from the GBM may contribute to proteinuria and progressive glomerulosclerosis [127-130]. In many glomerular disorders that are characterized by hypertrophy, the volume of the glomerular tuft increases, despite the decrease in podocyte number [129]. The resulting decrease in podocyte density causes areas of denuded GBM, which are foci for adhesions to parietal epithelial cells and eventual crescent formation [128].
Glomerular filtration subjects podocytes to both tensile and shear stress. Attachment of podocytes through interactions among the actin cytoskeleton, the underlying GBM, and integrins protects against tensile stress. Shear stress increases as filtration rate and filtration fraction increase, producing forces on lateral walls of opposing foot processes as well as on podocyte cell bodies. Protection against shear stress and podocyte detachment is thought to be provided by the slit diaphragm [131]. As the hydrostatic and hence shear pressures are highest at the beginning of the glomerular capillary tuft, it has been postulated that podocytes in this region may be the most prone to injury, helping to explain the heterogeneity of podocyte damage that occurs in diseases such as FSGS and why RAS blockade is so effective at protecting against podocyte injury. Some experts have hypothesized that as the filtration and shear stress become close to the danger level for detachment, podocytes respond by effacement, effectively converting the slit diaphragm to a tight junction, which will help prevent massive widening of the slit [58,59].
Podocytes and their specific molecular markers have been identified in urine from patients and rodent disease models, providing a possible readout for podocyte detachment and a biomarker for podocyte depletion and glomerular injury [132]. The presence of podocyte-specific messenger RNAs (mRNAs) in the urine may result from shed podocytes and/or exosomes or microvesicles derived from podocytes.
Proteinuria as a toxin — Although massive proteinuria may occur in the absence of obvious structural change in the slit diaphragm and foot processes, a sustained proteinuria event is invariably eventually associated with foot process effacement [79,133-136]. The mechanism underlying this phenomenon is unclear. One possibility is that exposure of podocytes to an increased concentration of albumin and immunoglobulin G (IgG) is sufficient to induce changes in the cytoskeleton [137].
SUMMARY
●Glomerular capillary wall – The glomerular capillary wall consists of the fenestrated capillary endothelium, glomerular basement membrane (GBM), and glomerular podocytes (or epithelial cells). Defects in any of the three components of the glomerular capillary wall can lead to proteinuria. (See 'Glomerular capillary wall' above.)
●Podocytes – Glomerular podocytes are terminally differentiated epithelial cells that have large cell bodies and long primary or major processes. The primary processes attach to the underlying GBM via multiple foot processes. (See 'Podocytes' above.)
•Slit diaphragm – The interdigitating foot processes of adjacent podocytes are joined laterally by slit diaphragms that bridge the intervening filtration slits. A number of proteins have been found to comprise the slit diaphragm; these include nephrin, neph1, neph2, FAT1, FAT2, podocin, transient receptor potential cation channel 6 (TRPC6), and tight junction proteins. (See 'Slit diaphragm' above.)
•Foot process effacement – Foot process effacement of glomerular podocytes is a characteristic histologic finding associated with glomerular diseases affecting the podocyte. Rearrangement of the actin cytoskeleton is necessary for foot process effacement to occur. (See 'Foot process effacement and cytoskeleton rearrangement' above.)
•Cytoskeletal arrangement – Possible molecular mechanisms underlying cytoskeletal rearrangement include phosphorylation/dephosphorylation of nephrin and cleavage of dynamin (a GTPase protein) by cathepsin-L. Activation of the urokinase receptor (uPAR) and initiation of beta3 integrin signaling may also be involved. (See 'Foot process effacement and cytoskeleton rearrangement' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Pierre Ronco, MD, who contributed to a previous version of this topic review.
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