Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process Effacement

Ma, Hong; Togawa, Akashi; Soda, Kunitsugu; Zhang, Junhui; Lee, Sik; Ma, Ming; Yu, Zhiheng; Ardito, Thomas; Czyzyk, Jan; Diggs, Lonnette; Joly, Dominique; Hatakeyama, Shinji; Kawahara, Eiji; Holzman, Lawrence B.; Guan, Jun; Ishibe, Shuta

doi:10.1681/asn.2009090991

Cited by 116 publications

(139 citation statements)

References 59 publications

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“…4F), although phospho-Fak Tyr-397 was lower following Cre recombination. These results suggest that active Ctnnb1 expression was associated with decreased adhesiveness in podocytes, which could be due to the decrease in Itgb1 expression and focal adhesion kinase (FAK) phosphorylation (38).…”

Section: /Ctnnb1mentioning

confidence: 87%

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Kato

Gruenwald

Suh

et al. 2011

Journal of Biological Chemistry

176

193

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Diabetic kidney disease (DKD) is the single most common cause of albuminuria and end-stage kidney disease in the UnitedStates. We found increased expression of Wnt/␤-catenin (Ctnnb1) pathway transcripts and proteins in glomeruli and podocytes of patients and mouse models of DKD. Mice with podocyte-specific expression of stabilized Ctnnb1 exhibited basement membrane abnormalities, albuminuria, and increased susceptibility to glomerular injury. Mice with podocyte-specific deletion of Ctnnb1 or podocyte-specific expression of the canonical Wnt inhibitor Dickkopf-related protein 1 (Dkk1) also showed increased susceptibility to DKD. Podocytes with stabilized Ctnnb1 were less motile and less adhesive to different matrices. Deletion of Ctnnb1 in cultured podocytes increased the expression of podocyte differentiation markers and enhanced cell motility; however, these cells were more susceptible to apoptosis. These results indicate that Wnt/Ctnnb1 signaling in podocytes plays a critical role in integrating cell adhesion, motility, cell death, and differentiation. Balanced Ctnnb1 expression is critical for glomerular filtration barrier maintenance. Diabetic kidney disease (DKD)2 is one of the most devastating complications of diabetes and the single most common cause of albuminuria, chronic kidney disease, and end-stage renal disease (ESRD) in the Western world (1). DKD causes filtration unit dysfunction leading to the development of albuminuria, which is the most abundant protein component of the blood. The glomerular filtration barrier consists of three layers as follows: glomerular endothelial cells, the glomerular basement membrane (GBM), and the glomerular epithelial cell (or podocyte) layer (2-4). Decreased glomerular podocyte density is shown to be the strongest predictor for end-stage renal disease development in patients with diabetes (5). Hyperglycemia via the generation of reactive oxygen species induces podocyte apoptosis and loss, which has been well documented in many different mouse DKD models (6, 7). As podocytes are terminally differentiated cells, they are unable to proliferate; therefore, apoptosis or detachment can lead to podocyte deficiency, which in turn will lead to glomerulosclerosis development (8, 9). Early administration of drugs that prevent podocyte apoptosis has been shown to ameliorate DKD in rodent models; however, this may not be a clinically translatable strategy (6, 10). Another early lesion in diabetes is the thickening of the basement membrane. The role and mechanism of GBM thickening are not fully understood. It is speculated that GBM thickening could cause alterations in integrin expression, which could interfere with podocyte adhesiveness. Genetic deletion of podocyte-specific integrins, Itgb1 and Itga3, causes albuminuria and glomerulosclerosis; however, the contribution of podocyte adhesion to DKD development has not been demonstrated (11,12). Understanding the mechanism of podocyte differentiation, adhesion and cell death could be highly relevant for the development of targets f...

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Section: /Ctnnb1mentioning

confidence: 87%

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Kato

Gruenwald

Suh

et al. 2011

Journal of Biological Chemistry

176

193

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“…The solution within the first passage resulted in the enrichment of the glomerulus and, after aspiration, was centrifuged at 600 g for 5 minutes at 4°C to remove the Percoll solution. Subculture of primary podocytes was performed by detaching the glomerular cells with 0.25% trypsin-EDTA (Invitrogen), followed by sieving through a 40-mm-cell strainer (Falcon, BD Biosciences) and culturing on collagen type I-coated dishes as previously described (Ma et al 2010). Podocytes of passages 1 or 2 were used in all experiments.…”

Section: Cell Culturementioning

confidence: 99%

“…41 Mice were briefly preimmunized 3 days before administration of NTS via intraperitoneal injection of 250 mg of rabbit IgG (Jackson Immunoresearch Laboratories) in 250 ml of 1:1 emulsion with complete Freund adjuvant (Sigma-Aldrich).…”

Section: Nts Glomerular Sample Preparationmentioning

confidence: 99%

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Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Hassan

Tian²,

Inoue³

et al. 2016

Journal of the American Society of Nephrology

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Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum. Furthermore, simultaneous podocyte-specific genetic inactivation of X-box binding protein-1 (Xbp1), a transcription factor activated during endoplasmic reticulum stress and critically involved in the untranslated protein response, and Sec63, a heat shock protein-40 chaperone required for protein folding in the endoplasmic reticulum, resulted in progressive albuminuria, foot process effacement, and histology consistent with ESRD. Finally, loss of both Sec63 and Xbp1 induced apoptosis in podocytes, which associated with activation of the JNK pathway. Collectively, our results indicate that an intact Xbp1 pathway operating to mitigate stress in the endoplasmic reticulum is essential for the maintenance of a normal glomerular filtration barrier.

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“…162 Similarly, podocyte-specific FAK knockout or an FAK inhibitor was protective in mice against proteinuria and foot-process effacement induced by podocyte insults (Figure 3). 163 Thus, integrin/FAK pathways appear to have important roles in normal podocyte physiology and pathology. In the meantime, the quest for humoral permeability factor(s) for minimal change disease and idiopathic FSGS needs to continue, including the validation of already-discovered molecules in broader patient populations.…”

Section: Future Direction Of Podocyte Biologymentioning

confidence: 99%

Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton

Kumagai¹,

Mouawad²,

Takano³

2012

CHC

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Abstract:Glomerulus is the filtration unit of the kidney where the first step of urine formation takes place. In the glomerulus, water and small molecules including waste products of the body are filtered into the urine, while large molecules essential for body function such as albumin are retained. When this barrier function of the kidney is impaired, protein leakage into the urine (proteinuria) occurs. Proteinuria is not only a hallmark of many glomerular diseases but also a prognostic marker of kidney disease progression. Visceral glomerular epithelial cells (commonly called podocytes) are known to have an important role in the maintenance of glomerular barrier function. In the last decade, remarkable progress has been made in podocyte biology, mainly led by the discoveries of important proteins that work together to maintain the intricate morphology and function of podocytes. Most of these so-called podocyte proteins modulate the actin cytoskeleton either directly or indirectly. The aim of the current review is to discuss the pathogenesis of common glomerular diseases with a particular focus on the role of the actin cytoskeleton in podocytes. The diseases covered include minimal change disease, focal segmental glomerulosclerosis (idiopathic and hereditary), membranous nephropathy, hypertensive glomerulosclerosis, and diabetic nephropathy.

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Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process Effacement

Cited by 116 publications

References 59 publications

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton

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Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process Effacement

Cited by 116 publications

References 59 publications

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Pathogenesis of common glomerular diseases &ndash; role of the podocyte cytoskeleton

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Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton