A Potential Role for Mechanical Forces in the Detachment of Podocytes and the Progression of CKD

Kriz, Wilhelm; Lemley, Kevin V.

doi:10.1681/asn.2014030278

Cited by 231 publications

(218 citation statements)

References 76 publications

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“…To balance this deficit, podocytes compensate by hypertrophy to cover more of the glomerular capillary surface. In a recent insightful and provocative review, Kriz and Lemley (42) proposed that shear stress forces on podocytes are a critical factor driving podocyte injury. In adaptive FSGS, glomerular hypertrophy occurs early in the disease process; in other forms of FSGS and other glomerular diseases, glomerular hypertrophy occurs with progressive nephron loss, leading to increased pressures and flows in the remaining patent glomeruli.…”

Section: Mechanisms Of Diseasementioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

416

366

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Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Section: Mechanisms Of Diseasementioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

416

366

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“…With time, the loss of podocyte contractile tone and adhesiveness causes the GBM to characteristically protrude at its external aspect closest to podocytes, and similarly, the capillary loops become more prone to gross dilation. 33 The bulging of the GBM and ballooning of the glomerular tuft are among the most striking pathologies in nephrin Y3F/Y3F mice, and analogous structures have been reported in mice lacking other podocyte proteins essential for binding to actin or the GBM. 29,[40][41][42][43][44] An additional characteristic of nephrin Y3F/Y3F animals is the disorganized patterning of foot processes.…”

Section: Discussionmentioning

confidence: 85%

“…The actin cytoskeleton is proposed to serve as a mechanotransduction apparatus to facilitate tight coregulation of podocyte contractility and GBM adhesion in response to fluctuating hemodynamic forces during filtration. 33,34 Crucial intermediates that link the slit diaphragm and GBM together with the cytoskeletal backbone are the PINCH-ILK-parvin complex and a-actinin-4. 35,36 Of note, Nck can complex with PINCH-ILK, 37 and it plays a direct role in cell adhesion and spreading.…”

Section: Discussionmentioning

confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin Y3F/Y3F mice). Homozygous nephrin Y3F/Y3F mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin Y3F/Y3F mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.

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“…Apart from necrosis, apoptosis or mitotic catastrophe, migration of podocytes onto Bowman's capsule, has been suggested as a novel mechanism of podocytes loss (109,110). Interestingly, unilateral ureteral obstruction results in better preservation of podocytes during glomerular injury suggesting biomechanics as an important factor (111,112).…”

Section: The Role Of Glomerular Cellsmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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A Potential Role for Mechanical Forces in the Detachment of Podocytes and the Progression of CKD

Cited by 231 publications

References 76 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

Renal Allograft Fibrosis: Biology and Therapeutic Targets

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