Novel role of Vav1-Rac1 pathway in actin cytoskeleton regulation in interleukin-13-induced minimal change-like nephropathy

Podocyte foot process effacement and proteinuria seen in our interleukin-13 (IL-13) overexpression rat model of minimal change-like nephropathy was associated with marked down-regulation of podocyte-related genes and activation of Vav1-Rac1-induced actin cytoskeleton rearrangement in the podocytes.

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Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-κB/JNK: a possible role of P-glycoprotein

Inflammopharmacology ◽

10.1007/s10787-019-00628-y ◽

2019 ◽

Vol 28 (1) ◽

pp. 215-230 ◽

Cited By ~ 5

Author(s):

Yasmine F. Ibrahim ◽

Rabab A. Moussa ◽

Asmaa M. A. Bayoumi ◽

Al-Shaimaa F. Ahmed

Keyword(s):

Rat Model ◽

Down Regulation ◽

P Glycoprotein ◽

Lung And Kidney

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Transfection of nonmuscle beta- and gamma-actin genes into myoblasts elicits different feedback regulatory responses from endogenous actin genes

The Journal of Cell Biology ◽

10.1083/jcb.117.4.787 ◽

1992 ◽

Vol 117 (4) ◽

pp. 787-797 ◽

Cited By ~ 51

Author(s):

C Lloyd ◽

G Schevzov ◽

P Gunning

Keyword(s):

Actin Cytoskeleton ◽

Feedback Regulation ◽

Cytochalasin D ◽

Actin Gene ◽

Down Regulation ◽

Actin Genes ◽

Beta Actin ◽

Actin Mrna ◽

Actin Protein

We have examined the role of feedback-regulation in the expression of the nonmuscle actin genes. C2 mouse myoblasts were transfected with the human beta- and gamma-actin genes. In gamma-actin transfectants we found that the total actin mRNA and protein pools remained unchanged. Increasing levels of human gamma-actin expression resulted in a progressive down-regulation of mouse beta- and gamma-actin mRNAs. Transfection of the beta-actin gene resulted in an increase in the total actin mRNA and protein pools and induced an increase in the levels of mouse beta-actin mRNA. In contrast, transfection of a beta-actin gene carrying a single-point mutation (beta sm) produced a feedback-regulatory response similar to that of the gamma-actin gene. Expression of a beta-actin gene encoding an unstable actin protein had no impact on the endogenous mouse actin genes. This suggests that the nature of the encoded actin protein determines the feedback-regulatory response of the mouse genes. The role of the actin cytoskeleton in mediating this feedback-regulation was evaluated by disruption of the actin network with Cytochalasin D. We found that treatment with Cytochalasin D abolished the down-regulation of mouse gamma-actin in both the gamma- and beta sm-actin transfectants. In contrast, a similar level of increase was observed for the mouse beta-actin mRNA in both control and transfected cells. These experiments suggest that the down-regulation of mouse gamma-actin mRNA is dependent on the organization of the actin cytoskeleton. In addition, the mechanism responsible for the down-regulation of beta-actin may be distinct from that governing gamma-actin. We conclude that actin feedback-regulation provides a biochemical assay for differences between the two nonmuscle actin genes.

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Role of γ-Adducin in Actin Cytoskeleton Rearrangements in Podocyte Pathophysiology

AJP Renal Physiology ◽

10.1152/ajprenal.00423.2020 ◽

2020 ◽

Author(s):

Wenjun Gao ◽

Yedan Liu ◽

Letao Fan ◽

Baoying Zheng ◽

Joshua R. Jefferson ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Vascular Function ◽

Renal Cortex ◽

Transgenic Rats ◽

Focal Adhesion Proteins ◽

Foot Process ◽

And Function ◽

Cytoskeleton Rearrangements ◽

Renal Vascular

We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the FHH rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH.Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH.Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 DsiRNA and primary podocytes isolated from FHH rats. There were increased F/G-actin ratio and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, glomeruli and podocytes of FHH rats. The expression of Nephrin at the slit diaphragm and the levels of focal adhesion proteins ITGA3 and ITGB1 were decreased in the glomeruli of FHH rats. Cell migration was enhanced and adhesion was reduced in podocytes of FHH rats, as well as in immortalized mouse podocyte transfected with Add3 DsiRNA. Mean arterial pressures were similar in FHH and FHH.Add3 transgenic rats at 16-week of age; however, FHH rats exhibited enhanced proteinuria associated with podocyte foot process effacement. These results demonstrate that reduced ADD3 function in FHH rats alters baseline podocyte pathophysiology by rearrangement of the actin cytoskeleton at the onset of proteinuria in young animals.

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Minimal Change Disease and IgA Deposition: Separate Entities or Common Pathophysiology?

Case Reports in Nephrology ◽

10.1155/2013/268401 ◽

2013 ◽

Vol 2013 ◽

pp. 1-3

Author(s):

Brandon S. Oberweis ◽

Aditya Mattoo ◽

Ming Wu ◽

David S. Goldfarb

Keyword(s):

Iga Nephropathy ◽

Minimal Change Disease ◽

Minimal Change ◽

Dramatic Improvement ◽

Creatinine Ratio ◽

Urine Protein ◽

Common Cause ◽

History Of ◽

Foot Process

Introduction. Minimal Change Disease (MCD) is the most common cause of nephrotic syndrome in children, while IgA nephropathy is the most common cause of glomerulonephritis worldwide. MCD is responsive to glucocorticoids, while the role of steroids in IgA nephropathy remains unclear. We describe a case of two distinct clinical and pathological findings, raising the question of whether MCD and IgA nephropathy are separate entities or if there is a common pathophysiology.Case Report. A 19-year old man with no medical history presented to the Emergency Department with a 20-day history of anasarca and frothy urine, BUN 68 mg/dL, Cr 2.3 mg/dL, urinalysis 3+ RBCs, 3+ protein, and urine protein : creatinine ratio 6.4. Renal biopsy revealed hypertrophic podocytes on light microscopy, podocyte foot process effacement on electron microscopy, and immunofluorescent mesangial staining for IgA. The patient was started on prednisone and exhibited dramatic improvement.Discussion. MCD typically has an overwhelming improvement with glucocorticoids, while the resolution of IgA nephropathy is rare. Our patient presented with MCD with the uncharacteristic finding of hematuria. Given the improvement with glucocorticoids, we raise the question of whether there is a shared pathophysiologic component of these two distinct clinical diseases that represents a clinical variant.

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Temporal and Spatial Expression of Podocyte-Associated Molecules Are Accompanied by Proteinuria in IgA Nephropathy Rat Model

Physiological Research ◽

10.33549/physiolres.932380 ◽

2013 ◽

pp. 35-45 ◽

Cited By ~ 3

Author(s):

H.-Y. LU ◽

L.-Z. CHEN ◽

X.-Y. JIANG ◽

Y. MO ◽

Y.-H. LING ◽

...

Keyword(s):

Electron Microscopy ◽

Iga Nephropathy ◽

Rat Model ◽

Light And Electron Microscopy ◽

Urinary Protein ◽

Real Time Quantitative Pcr ◽

Renal Morphology ◽

Healthy Control ◽

Foot Process

We used a rat model to assess the role of nephrin, podocin, and desmin in the pathogenesis of IgA nephropathy (IgAN). A rat IgAN model was established by administration of BSA, CCl4, and lipopolysaccharide (LPS) and compared with healthy control rats. Urinary protein, urine red blood cells, and biochemical parameters were measured for 12 weeks. Renal morphology and ultrastructure were examined by light and electron microscopy. Immunofluorescence was used to assess IgA deposition in the glomeruli and to measure expression of nephrin, podocin, and desmin. Real-time quantitative PCR was used to measure expression of nephrin, podocin, and desmin mRNAs. IgAN rats developed proteinuria at week-6 and this worsened over time. Pathological changes were evident under light microscopy at week-8 and under electron microscopy at week-4. Immunofluorescence analysis showed deposition of IgA in the kidneys of IgAN rats, but not control rats. IgAN rats had increased expression of glomerular podocin, nephrin, and desmin mRNAs and proteins at week-4. The expression of nephrin, podocin and desmin proteins and the expression of podocin and desmin mRNAs preceded the increase in urinary protein. Taken together, our study of a rat model of IgAN indicates that changes in the expression and distribution of nephrin, podocin, and desmin precede and may cause foot process fusion and proteinuria.

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Mechanisms of Glomerular Albumin Filtration and Tubular Reabsorption

International Journal of Nephrology ◽

10.1155/2012/481520 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 89

Author(s):

Akihiro Tojo ◽

Satoshi Kinugasa

Keyword(s):

Early Stage ◽

Collecting Duct ◽

Distal Tubule ◽

Minimal Change Nephrotic Syndrome ◽

Minimal Change ◽

Membrane Rupture ◽

Filtration Barrier ◽

Podocyte Detachment ◽

Foot Process

Albumin is filtered through the glomerulus with a sieving coefficient of 0.00062, which results in approximately 3.3 g of albumin filtered daily in human kidneys. The proximal convoluted tubule reabsorbs 71%, the loop of Henle and distal tubule 23%, and collecting duct 3% of the glomerular filtered albumin, thus indicating that the kidney plays an important role in protein metabolism. Dysfunction of albumin reabsorption in the proximal tubules, due to reduced megalin expression, may explain the microalbuminuria in early-stage diabetes. Meanwhile, massive nonselective proteinuria is ascribed to various disorders of the glomerular filtration barrier, including podocyte detachment, glomerular basement membrane rupture, and slit diaphragm dysfunction in focal segmental glomerulosclerosis, membranous nephropathy, and other glomerulonephritis. Selective albuminuria associated with foot process effacement and tight junction-like slit alteration is observed in the patients with minimal-change nephrotic syndrome, and the albumin uptake is enhanced in the podocyte cell body, possibly mediated by albumin receptors in the low-dose puromycin model. The role of enhanced podocyte albumin transport needs to be investigated to elucidate the mechanism of the selective albuminuria in minimal-change disease.

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Role of Transient Receptor Potential Canonical Channel 6 (TRPC6) in Diabetic Kidney Disease by Regulating Podocyte Actin Cytoskeleton Rearrangement

Journal of Diabetes Research ◽

10.1155/2020/6897390 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Qian Wang ◽

Xuefei Tian ◽

Yuyang Wang ◽

Yan Wang ◽

Jialin Li ◽

...

Keyword(s):

Kidney Disease ◽

Actin Cytoskeleton ◽

Diabetic Kidney Disease ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Diabetic Kidney ◽

Transient Receptor Potential Canonical ◽

Transient Receptor ◽

Cytoskeleton Rearrangement

Podocyte injury is an important pathogenesis step causing proteinuric kidney diseases such as diabetic kidney disease (DKD). Actin cytoskeleton rearrangement in podocyte induced by multiple pathogenic factors is believed to be the key process resulting in glomerular injury. Many studies have recently shown that transient receptor potential canonical channel 6 (TRPC6) in podocyte plays a critical role in the development and progression of proteinuric kidney disease by regulating its actin cytoskeleton rearrangement. This review is aimed at summarizing the role of TRPC6 on DKD by regulating the podocyte actin cytoskeleton rearrangement, thereby help further broaden our views and understanding on the mechanism of DKD and provide a theoretic basis for exploring new therapeutic targets for DKD patients.

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Angiopoietin-Like 3 Induces Podocyte F-Actin Rearrangement through IntegrinαVβ3/FAK/PI3K Pathway-Mediated Rac1 Activation

BioMed Research International ◽

10.1155/2013/135608 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Yi Lin ◽

Jia Rao ◽

Xi-liang Zha ◽

Hong Xu

Keyword(s):

Actin Cytoskeleton ◽

Pi3k Pathway ◽

Small Gtpases ◽

Glomerular Diseases ◽

Differentiated Cells ◽

Foot Process ◽

Rho Family ◽

Actin Rearrangement ◽

Cytoskeleton Rearrangement

Glomerular podocytes are highly differentiated cells whose foot processes, which are mainly maintained by the architecture of actin filaments, have a unique morphology. A rearrangement of F-actin in podocytes causes changes in their motility that involve foot process effacement and proteinuria in glomerular diseases. Members of the Rho family small GTPases, especially RhoA, Rac1, and Cdc42, are key molecules in the regulation of actin cytoskeleton rearrangement. Our previous study showed that angiopoietin-like 3 (Angptl3) can increase the motility of podocytesin vitro. In this study, we found that recombinant Angptl3 treatment, together with the activation of Rac1, could cause F-actin rearrangement in podocytes. We also found that these effects could be blocked by an integrinαVβ3inhibitor, implicating integrinαVβ3as the Angptl3 receptor in its effects on actin cytoskeleton rearrangement. In addition, we studied the molecular pathway for this process. Our results showed that in podocytes, Angptl3 could induce actin filament rearrangement, mainly in lamellipodia formation, and that this process was mediated by integrinαVβ3-mediated FAK and PI3K phosphorylation and Rac1 activation. Our results might provide a new explanation for the effect of Angptl3 on increasing podocyte motility.

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