Expression of  -actinin-4 in acquired human nephrotic syndrome: a quantitative immunoelectron microscopy study

Goode, N. P.; Shires, Michael; Khan, Tahir Naeem; Mooney, Andrew

doi:10.1093/ndt/gfg620

Cited by 23 publications

(16 citation statements)

References 18 publications

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“…Our results from WT kidneys that were transplanted into Cfh Ϫ/Ϫ hosts provide compelling data that mouse podocytes produce Cfh in vivo. In this setting, there is absent plasma Cfh and only small quantities of total renal Cfh, yet Cfh in glomeruli is closely associated with the podocyte ␣-actinin 4 protein, present in their "soles" adjacent to the glomerular basement membrane (55). Particularly because Cfh lacks a membrane-spanning region, whether it is an intrinsic podocyte membrane protein such as CR1 or is just in the vicinity of the podocyte cell membrane cannot be stated for certainty.…”

Section: Discussionmentioning

confidence: 98%

Mouse Podocyte Complement Factor H

Alexander¹,

Wang²,

Chang

et al. 2007

Journal of the American Society of Nephrology

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Complement factor H (Cfh) is a key plasma protein in humans and animals that serves to limit alternative pathway complement activation in plasma, as well as in local sites such as capillaries of the glomerulus and eye. It was shown that rodent Cfh on platelets is the functional analogue to human erythrocyte complement receptor 1 with a role that is distinct from plasma Cfh and that Cfh is also on cultured rodent podocytes. For investigation of the role of Cfh in the kidney, renal transplants were performed between wild-type (WT) and Cfh Ϫ/Ϫ C57BL/6 mice. For these studies, bilateral native nephrectomies were done so that renal function was dependent solely on the transplanted kidney. Chronic serum sickness was induced by active immunization with apoferritin. Diffuse proliferative glomerulonephritis (GN) occurred in WT kidneys that were transplanted into Cfh Ϫ/Ϫ recipients (n ‫؍‬ 8) but not into WT recipients (n ‫؍‬ 14), consistent with the importance of plasma Cfh to dictate outcome in this disease model. Relative to the WT recipients of WT kidneys, WT mice with Cfh Ϫ/Ϫ kidneys (n ‫؍‬ 12) developed glomerular disease features, including increased albuminuria (82.8 ؎ 7.0 versus 45.1 ؎ 3.6 g/mg creatinine; P < 0.001) and blood urea nitrogen levels (54.4 ؎ 6.1 versus 44.2 ؎ 3.7 mg/dl; P < 0.01). In addition, they had substantial glomerular capillary wall deposits of IgG and C3, which by electron microscopy were present in subendothelial and subepithelial immune deposits, whereas WT kidneys in WT hosts had almost exclusive mesangial deposits. The IgG deposits in Cfh Ϫ/Ϫ kidneys were adjacent to Cfh-deficient podocytes, whereas WT kidneys in a Cfh Ϫ/Ϫ host had podocyte-associated Cfh with absent IgG deposits. These data suggest that locally produced podocyte Cfh is important to process immune complexes in the subepithelial space, where it also limits complement activation. Just as in platelets, rodent podocytes seem to use Cfh as the functional surrogate for human complement receptor 1.

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Section: Discussionmentioning

confidence: 98%

Mouse Podocyte Complement Factor H

Alexander¹,

Wang²,

Chang

et al. 2007

Journal of the American Society of Nephrology

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“…In contrast, ACTN4 is absent from adhesion plaques or junctions (37), and its interaction with actin is Ca 2ϩ -insensitive (59 -61). ACTN4 is found at dorsal surface ruffles in macrophages (62) and plasma membranes in podocytes (63) and participates in cell motility, exosome formation (64), and transferrin receptor recycling (44).…”

Section: Discussionmentioning

confidence: 99%

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

Talior-Volodarsky

Randhawa

Zaid

et al. 2008

Journal of Biological Chemistry

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Insulin induces GLUT4 translocation to the muscle cell surface. Using differential amino acid labeling and mass spectrometry, we observed insulin-dependent co-precipitation of actinin-4 (ACTN4) with GLUT4 (Foster, L. J., Rudich, A., Talior, I., Patel, N., Huang, X., Furtado, L. M., Bilan, P. J., Mann, M., and Klip, A. (2006) J. Proteome Res. 5, 64 -75). ACTN4 links F-actin to membrane proteins, and actin dynamics are essential for GLUT4 translocation. We hypothesized that ACTN4 may contribute to insulin-regulated GLUT4 traffic. In L6 muscle cells insulin, but not platelet-derived growth factor, increased co-precipitation of ACTN4 with GLUT4. Small interfering RNA-mediated ACTN4 knockdown abolished the gain in surface-exposed GLUT4 elicited by insulin but not by platelet-derived growth factor, membrane depolarization, or mitochondrial uncoupling. In contrast, knockdown of ␣-actinin-1 (ACTN1) did not prevent GLUT4 translocation by insulin. GLUT4 colocalized with ACTN4 along the insulin-induced cortical actin mesh and ACTN4 knockdown prevented GLUT4-actin colocalization without impeding actin remodeling or Akt phosphorylation, maintaining GLUT4 in a tight perinuclear location. We propose that ACTN4 contributes to GLUT4 traffic, likely by tethering GLUT4 vesicles to the cortical actin cytoskeleton. Insulin-regulated glucose transporter 4 (GLUT4)4 is a member of the SLC2A facilitative glucose transporter family (2) and is responsible for glucose entry into muscle and fat tissues (3-5). GLUT4 continuously cycles to/from the cell membrane through a series of endosomal compartments. In response to insulin there is a rapid increase in the steady-state level of GLUT4 at the cell surface, at the expense of intracellular pools (6 -9). This process is defective in insulin resistance and type 2 diabetes (10 -12). Stimuli other than insulin such as muscle contraction, depolarization, or hypoxia also increase surface GLUT4 (13-16). Whereas insulin largely increases the exocytic arm of GLUT4 cycling (17), hypoxia or membrane depolarization preferentially reduce GLUT4 endocytosis in muscle cells (16,18,19). Moreover, although insulin-dependent GLUT4 translocation requires dynamic remodeling of filamentous actin (20 -23), the gain in surface GLUT4 elicited by plateletderived growth factor (PDGF), depolarization, or mitochondrial uncouplers is independent of actin dynamics (24 -26).Intensive research has recently focused on identifying the individual mechanisms participating in GLUT4 traffic and the specific events regulated by insulin (27)(28)(29)(30)(31). Hypothesizing that GLUT4 traffic may be regulated by interaction with partner proteins, it is of fundamental and clinical interest to identify such proteins. Accordingly, we recently applied the novel SILAC (stable isotope labeling by amino acids in cell culture) approach (32) to search for proteins that associate with GLUT4 in an insulin-regulated manner (1). The study took advantage of the stable expression in L6 muscle cells of GLUT4 encoding an myc tag that faces the extrace...

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“…Actn4-deficient Podocytes Have Weaker Integrin-Cytoskeleton Linkages-␣-Actinin-4 is expressed in the foot processes of human podocytes near the basement membrane, as detected by immunoelectron microscopy (61). ␣-Actinins also interact directly with the cytoplasmic domain of ␤-integrins (16,19) within focal adhesion anchoring complexes that govern the strength of cell adhesions (62).…”

Section: Figure 2 Podocyte Number Per Glomerulus Is Decreased In Actn4mentioning

confidence: 99%

α-Actinin-4 Is Required for Normal Podocyte Adhesion

Dandapani

Sugimoto

Matthews

et al. 2007

Journal of Biological Chemistry

115

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Mutations in the ␣-actinin-4 gene ACTN4 cause an autosomal dominant human kidney disease. Mice deficient in ␣-actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes. However, the mechanism by which ␣-actinin-4 deficiency leads to glomerular disease has not been defined. Here, we examined the effect of ␣-actinin-4 deficiency on the adhesive properties of podocytes in vivo and in a cell culture system. In ␣-actinin-4-deficient mice, we observed a decrease in the number of podocytes per glomerulus compared with wild-type mice as well as the presence of podocyte markers in the urine. Podocyte cell lines generated from ␣-actinin-4-deficient mice were less adherent than wild-type cells to glomerular basement membrane (GBM) components collagen IV and laminin 10 and 11. We also observed markedly reduced adhesion of ␣-actinin-4-deficient podocytes under increasing shear stresses. This adhesion deficit was restored by transfecting cells with ␣-actinin-4-GFP. We tested the strength of the integrin receptor-mediated linkages to the cytoskeleton by applying force to microbeads bound to integrin using magnetic pulling cytometry. Beads bound to ␣-actinin-4-deficient podocytes showed greater displacement in response to an applied force than those bound to wild-type cells. Consistent with integrin-dependent ␣-actinin-4-mediated adhesion, phosphorylation of ␤1-integrins on ␣-actinin-4-deficient podocytes is reduced. We rescued the phosphorylation deficit by transfecting ␣-actinin-4 into ␣-actinin-4-deficient podocytes. These results suggest that ␣-actinin-4 interacts with integrins and strengthens the podocyte-GBM interaction thereby stabilizing glomerular architecture and preventing disease.

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Expression of -actinin-4 in acquired human nephrotic syndrome: a quantitative immunoelectron microscopy study

Abstract: Elevated alpha-actinin-4 expression is observed only in MGN, and only in areas of subepithelial deposits. Further investigation into the cause of this may reveal insights into the pathogenesis of acquired nephrosis.

Cited by 23 publications

References 18 publications

Mouse Podocyte Complement Factor H

Mouse Podocyte Complement Factor H

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

α-Actinin-4 Is Required for Normal Podocyte Adhesion

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