Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome

Smoyer, William E.; Mündel, Peter; Gupta, Avneesh; Welsh, Michael J.

doi:10.1152/ajprenal.1997.273.1.f150

Cited by 84 publications

(96 citation statements)

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“…Several reports have documented an abnormal distribution and disaggregation of podocyte actin microfilaments during the development of foot process effacement (30 -32). Concomitant redistribution of actin and ␣-actinin in the podocytes of nephrotic rats has also been reported (30,33), resulting in dysregulation of actin filament bundling in foot processes and finally yielding disruption of normal foot process function. Such alterations in cytoskeletal function might explain the characteristic changes to podocytes observed in FSGS.…”

Section: Discussionmentioning

confidence: 92%

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Michaud

Lemieux²,

Dubé

et al. 2003

Journal of the American Society of Nephrology

144

124

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Abstract. Mutations in the gene encoding ␣-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine ␣-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant ␣-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vacuolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant ␣-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.

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Section: Discussionmentioning

confidence: 92%

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Michaud

Lemieux²,

Dubé

et al. 2003

Journal of the American Society of Nephrology

144

124

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“…Generally, in the current study, the protein expression of most podocyte-associated molecules was diminished in acquired proteinuric diseases, coinciding with an increase in mRNA levels. A divergence between mRNA and protein levels has been described for synaptopodin and ␣-actinin 4 in patients with nephrotic syndromes (24,44) and in podocyte-associated molecules in the PAN nephrosis rat model (37,45). There was no direct correlation between the level of proteinuria and the protein and mRNA expression of the molecules studied.…”

Section: Discussionmentioning

confidence: 93%

“…In PAN nephrosis of the rat, mRNA levels of molecules that bind the podocyte to the GBM are increased, suggesting an effort of the podocytes to remain attached to the GBM (37). Similarly, in human and experimental proteinuric states, the mRNA expression of ␣-actinin 4 is increased, probably reflecting a compensatory reaction of the podocyte (44,45). The rise in mRNA levels of nephrin, podocin, and podoplanin might likewise result from a compensatory reaction to the damage inflicted on the podocyte.…”

Section: Discussionmentioning

confidence: 99%

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

Koop¹,

Eikmans²,

Baelde³

et al. 2003

Journal of the American Society of Nephrology

272

200

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Abstract. Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied, including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r ϭ Ϫ0.443, P Ͻ 0.05), whereas it was positively correlated with podoplanin mRNA levels (r ϭ 0.468, P Ͻ 0.05) and proteinuria (r ϭ 0.585, P ϭ 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.

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“…␣3␤1-Integrin has been shown to be expressed on glomerular podocytes and to be important in attaching podocytes to the glomerular basement membrane components (44,(52)(53)(54)(55)(56)(57). In particular, anti-Fx1A, an ␣3␤1-integrin blocking antibody was found to block adhesion of rat glomerular epithelial cells to collagen, laminin, and fibronectin with the greatest observed effect on blocking adhesion to collagen IV (44).…”

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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Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome

Cited by 84 publications

References 0 publications

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

α-Actinin-4 Is Required for Normal Podocyte Adhesion

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