Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin

Schwarz, Karin; Simons, Matias; Reiser, Jochen; Saleem, Moin A.; Faul, Christian; Kriz, Wihelm; Shaw, Andréy S.; Holzman, Lawrence B.; Mündel, Peter

doi:10.1172/jci200112849

Cited by 512 publications

(353 citation statements)

References 41 publications

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“…Cholesterol overload from its elevated carriers i.e . circulating LDLs, as was shown in the present study, might negatively influence the binding of podocyte SD proteins to each other, as which is assembled in lipid rafts and is playing a critical role in the formation of glomerular filtration barrier and maintenance of the interdigitating foot process pattern 42, 46, 47. We found in vivo and in vitro , SD proteins podocin and NEPH1 were dramatically decreased during the challenge of hypercholesterolaemia or ox‐LDL treatment.…”

Section: Discussionsupporting

confidence: 73%

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Fan

Zhen

et al. 2016

J Cellular Molecular Medi

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Focal adhesion kinase (FAK) is a non‐receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet‐induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder‐related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c‐Src, Rho GTPase and mitogen‐activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low‐density lipoprotein (ox‐LDL) triggered hyper‐phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re‐arrangement of F‐actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre‐treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper‐activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox‐LDL damaged podocytes in a FAK/p38‐dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia‐related podocyte damage and proteinuria.

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Section: Discussionsupporting

confidence: 73%

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Fan

Zhen

et al. 2016

J Cellular Molecular Medi

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“…The external, highly glycosylated, Ig-like domain of nephrin forms dimers across the slit diaphragm, producing pores with a predicted diameter slightly smaller than the radius of albumin [20] and regulates glomerular permeability [15]. Podocin is another component of the slit diaphragm and its COOH-terminal cytoplasmic domain interacts with CD2AP and nephrin [21]. Podocin may serve two closely related functions: the recruitment and/or stabilization of nephrin at the podocyte foot process, and the augmentation of nephrin signaling, perhaps by organizing specialized nephrin-containing microdomains [22].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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Section: Introductory Paragraphmentioning

confidence: 99%

“…On the basis of its predicted structure, podocin belongs to the stomatin protein family, with a hairpin-like intramembrane loop and intracellular N and C termini. The C-terminal portions of both stomatin and podocin are responsible for dimerization 6,[8][9][10][11][12] .Individuals with NPHS2 mutations typically develop SRNS before 6 years of age and progress to ESRD during their first decade of life6. The phenotype can be less severe in the setting of a trans association of an NPHS2 mutation and the polymorphism c.686G>A (p.Arg229Gln, rs61747728), a genotype we hereafter denote as p.…”

mentioning

confidence: 99%

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

et al. 2014

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Abbreviations: NPHS2: nephrosis 2, steroid-resistant ; SRNS: steroid-resistant nephrotic syndrome Introductory paragraphNephrotic syndrome is the consequence of damage to the glomerular filtration barrier, and it refers to the clinical symptoms of heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. The steroidresistant form of nephrotic syndrome (SRNS) has a poor prognosis, as it often leads to endstage renal disease (ESRD) 1,2 . Mutations in more than 20 genes have been identified in monogenic forms of SRNS, most of which encode podocyte proteins3-5. NPHS2, encoding podocin, is the most frequently mutated of these genes and is responsible for 12-18% of SRNS cases 3,6,7 . Podocin accumulates in dimeric or oligomeric forms in lipid raft microdomains at the podocyte slit diaphragm, which is the key component of the glomerular filtration barrier. On the basis of its predicted structure, podocin belongs to the stomatin protein family, with a hairpin-like intramembrane loop and intracellular N and C termini. The C-terminal portions of both stomatin and podocin are responsible for dimerization 6,[8][9][10][11][12] .Individuals with NPHS2 mutations typically develop SRNS before 6 years of age and progress to ESRD during their first decade of life6. The phenotype can be less severe in the setting of a trans association of an NPHS2 mutation and the polymorphism c.686G>A (p.Arg229Gln, rs61747728), a genotype we hereafter denote as p.[Arg229Gln];[mut] that causes SRNS with a median age at diagnosis of 13 years (range, 0-39 years) and progression to ESRD by 26 years (range, 10-50 years) 7,[13][14][15][16][17][18] . Nevertheless, the p.Arg229Gln variant in the homozygous state does not cause SRNS 19,20 .On the basis of the 15× higher allele frequency of p.Arg229Gln (357/13,006, 2.7%) than the cumulative allele frequency of the known disease-causing variants 13-18,21-43 (24/13,006, 0.18%)

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Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin

Cited by 512 publications

References 41 publications

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Podocyte Mitosis – A Catastrophe

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

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