scholarly journals Nucleoporin 133 deficiency leads to glomerular damage in zebrafish

2018 ◽  
Author(s):  
Chiara Cianciolo Cosentino ◽  
Alessandro Berto ◽  
Michelle Hari ◽  
Johannes Loffing ◽  
Stephan C. F. Neuhauss ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Development ◽  
Orthologous Gene ◽  
Hereditary Diseases ◽  
Nuclear Pore ◽  
Filtration Barrier ◽  
New Gene ◽  
Foot Process ◽  
Glomerular Development ◽  
And Function

AbstractAlthough structural nuclear pore proteins (nucleoporins) are seemingly required in every cell type to assemble a functional nuclear transport machinery, mutations or deregulation of a subset of them have been associated with specific human hereditary diseases. In particular, previous genetic studies of patients with nephrotic syndrome identified mutations inNup107that impaired the expression or the localization of its direct partner at nuclear pores, Nup133. In the present study, we characterized the zebrafishnup133orthologous gene and its expression pattern during larval development. Morpholino-mediated gene knockdown revealed that Nup133 depletion in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected bynup133knockdown. On the other hand, we demonstrate thatnup133is essential for the organization and functional integrity of the pronephric glomerular filtration barrier, as its downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome. These data indicate thatnup133is a new gene required for proper glomerular structure and function in zebrafish.

scholarly journals Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome

2018 ◽  
Vol 29 (5) ◽  
pp. 1426-1436 ◽  
Author(s):  
Meei-Hua Lin ◽  
Joseph B. Miller ◽  
Yamato Kikkawa ◽  
Hani Y. Suleiman ◽  
Karl Tryggvason ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Congenital Nephrotic Syndrome ◽  
Super Resolution ◽  
Diffuse Mesangial Sclerosis ◽  
Protein Therapy ◽  
Correct Orientation ◽  
Pierson Syndrome ◽  
Foot Process ◽  
And Function

Background Laminin α5β2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2−/− pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.

scholarly journals Mechanism Underlying Selective Albuminuria in Minimal Change Nephrotic Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Akihiro Tojo
Keyword(s):  
Nephrotic Syndrome ◽  
A Priori ◽  
Minimal Change Nephrotic Syndrome ◽  
Cytoplasmic Dynein ◽  
Minimal Change ◽  
Filtration Barrier ◽  
Urinary Protein Level ◽  
Foot Process ◽  
Albumin Receptor ◽  
Albumin Endocytosis

As water and solutes are filtered through the slit membrane, it is an a priori concept that a slit membrane is an essential filtration barrier for proteins, including albumin. However, in cases of minimal change nephrotic syndrome, the number of slit membranes is reduced by the foot process effacement and tight junction-like cell adhesion. Furthermore, albumin endocytosis is enhanced in the podocytes under condition of minimal change disease, and albumin is selectively transported by the albumin receptor FcRn. Suppressing the endocytosis of albumin with anti-FcRn antibody decreases the urinary protein level. The expression of motor molecules, such as cytoplasmic dynein 1 and myosin IX, is increased in the podocytes under conditions of minimal change nephrotic syndrome, suggesting the enhanced transport of vesicles containing albumin. Podocyte vesicle transport may play an important role in the pathology of selective albuminuria in cases of nephrotic syndrome.

scholarly journals Ste20-like kinase, SLK, a novel mediator of podocyte integrity

2018 ◽  
Vol 315 (1) ◽  
pp. F186-F198 ◽  
Author(s):  
Andrey V. Cybulsky ◽  
Joan Papillon ◽  
Julie Guillemette ◽  
Natalya Belkina ◽  
Genaro Patino-Lopez ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Plasma Membranes ◽  
Kidney Development ◽  
Kidney Injury ◽  
Ultrastructural Changes ◽  
Morphological Evidence ◽  
Foot Process ◽  
And Function ◽  
Specific Deletion

SLK is essential for embryonic development and may play a key role in wound healing, tumor growth, and metastasis. Expression and activation of SLK are increased in kidney development and during recovery from ischemic acute kidney injury. Overexpression of SLK in glomerular epithelial cells/podocytes in vivo induces injury and proteinuria. Conversely, reduced SLK expression leads to abnormalities in cell adhesion, spreading, and motility. Tight regulation of SLK expression thus may be critical for normal renal structure and function. We produced podocyte-specific SLK-knockout mice to address the functional role of SLK in podocytes. Mice with podocyte-specific deletion of SLK showed reduced glomerular SLK expression and activity compared with control. Podocyte-specific deletion of SLK resulted in albuminuria at 4–5 mo of age in male mice and 8–9 mo in female mice, which persisted for up to 13 mo. At 11–12 mo, knockout mice showed ultrastructural changes, including focal foot process effacement and microvillous transformation of podocyte plasma membranes. Mean foot process width was approximately twofold greater in knockout mice compared with control. Podocyte number was reduced by 35% in knockout mice compared with control, and expression of nephrin, synaptopodin, and podocalyxin was reduced in knockout mice by 20–30%. In summary, podocyte-specific deletion of SLK leads to albuminuria, loss of podocytes, and morphological evidence of podocyte injury. Thus, SLK is essential to the maintenance of podocyte integrity as mice age.

Platelet Suruival and Function in Rats with Enhanced Thrombotic Tendency

1985 ◽  
Vol 54 (04) ◽  
pp. 739-743 ◽  
Author(s):  
Federica Delaini ◽  
Elisabetta Dejana ◽  
Ine Reyers ◽  
Elisa Vicenzi ◽  
Germana De Bellis Vitti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Function ◽  
Laboratory Tests ◽  
Thrombus Formation ◽  
The Other ◽  
Mean Survival Time ◽  
The Mean ◽  
And Function ◽  
Thrombotic Tendency

SummaryWe have investigated the relevance of some laboratory tests of platelet function in predicting conditions of thrombotic tendency. For this purpose, we studied platelet survival, platelet aggregation in response to different stimuli, TxB2 and 6-keto-PGFlα production in serum of rats bearing a nephrotic syndrome induced by adriamycin. These animals show a heavy predisposition to the development of both arterial and venous thrombosis. The mean survival time was normal in nephrotic rats in comparison to controls. As to aggregation tests, a lower aggregating response was found in ADR-treated rats using ADP or collagen as stimulating agents. With arachidonic acid (AA) we observed similar aggregating responses at lower A A concentrations, whereas at higher AA concentrations a significantly lower response was found in nephrotic rats, despite their higher TxB2 production. Also TxB2 and 6-keto-PGFlα levels in serum of nephrotic rats were significantly higher than in controls. No consistent differences were found in PGI2-activity generated by vessels of control or nephrotic rats.These data show that platelet function may appear normal or even impaired in rats with a markedly increased thrombotic tendency. On the other hand, the significance of high TxB2 levels in connection with mechanisms leading to thrombus formation remains a controversial issue.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1815
Author(s):  
Jan Boeckhaus ◽  
Oliver Gross
Keyword(s):  
Glomerular Filtration ◽  
Alport Syndrome ◽  
Large Scale ◽  
Case Series ◽  
Hereditary Diseases ◽  
Glomerular Filtration Barrier ◽  
Early Effect ◽  
Filtration Barrier ◽  
First Case ◽  
Sodium Glucose Cotransporter

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

scholarly journals tRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Shanwen Li ◽  
Yiwen Liu ◽  
Xiaowei He ◽  
Xiagang Luo ◽  
Huimin Shi ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Signaling Pathway ◽  
Idiopathic Nephrotic Syndrome ◽  
Wnt Signaling Pathway ◽  
Differentially Expressed ◽  
Ras Signaling ◽  
Potential Mechanism ◽  
Significant Differential Expression ◽  
Podocyte Injury ◽  
Filtration Barrier

Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the potential mechanism of INS. Differentially expressed tRFs in the adriamycin-treated group were identified by high-throughput sequencing and further verified by quantitative RT-PCR. In total, 203 tRFs with significant differential expression were identified, namely, 102 upregulated tRFs and 101 downregulated tRFs (q<0.05, ∣log2FC∣≥2). In particular, AS-tDR-008924, AS-tDR-011690, tDR-003634, AS-tDR-013354, tDR-011031, AS-tDR-001008, and AS-tDR-007319 were predicted to be involved in podocyte injury by targeting the Gpr, Wnt, Rac1, and other genes. Furthermore, gene ontology analysis showed that these differential tRFs were strongly associated with podocyte injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton, and insulin-activate receptor activity. KEGG pathway analysis predicted that they participated in the PI3K-Akt signaling pathway, Wnt signaling pathway, and Ras signaling pathway. It was reported that these pathways contribute to podocyte injury. In conclusion, our study revealed that changes in the expression levels of tRFs might be involved in INS. Seven of the differentially expressed tRFs might play important roles in the process of podocyte injury and are worthy of further study.

scholarly journals Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis

2018 ◽  
Vol 314 (5) ◽  
pp. F921-F925 ◽  
Author(s):  
Di Feng ◽  
Clark DuMontier ◽  
Martin R. Pollak
Keyword(s):  
Blood Flow ◽  
Focal Segmental Glomerulosclerosis ◽  
Kidney Injury ◽  
Future Research ◽  
Disease States ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
The Face ◽  
Foot Process ◽  
Future Research Directions

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

Abstract 094: Pappa2 is Important for Determining the Nephron Number

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Vikash Kumar ◽  
Chun Yang ◽  
Aron M Geurts ◽  
Mingyu Liang ◽  
Allen W Cowley
Keyword(s):  
Mrna Expression ◽  
Kidney Development ◽  
Brown Norway ◽  
Ureteric Bud ◽  
Induced Hypertension ◽  
Allele Variant ◽  
Rat Strain ◽  
Nephron Development ◽  
And Function ◽  
Igfbp 3

Pappa2 is a metalloproteinase which specifically cleaves IGFBP-3 and IGFBP-5 and in turn releases IGF-1. Recently, we have shown that a subcongenic Dahl salt-sensitive (SS) rat strain containing a 0.71 Mbp of chromosome 13 which includes Pappa2 gene from salt-insensitive Brown Norway (26-P strain) is protected significantly (24 mmHg) from salt-induced hypertension (Cowley et al., 2016). Although it is recognized that Pappa2 modulates development of bone size, cranial cartilage and angiogenesis, its role in kidney development and function is unknown. The present study determined the contribution of Pappa2 to nephron development by comparing SS and 26-P rat strains. It was found that Pappa2 mRNA expression was 5-fold higher in embryonic kidney (day 20.5) of the salt-resistant 26-P rats compared with age-matched SS rats. Pappa2 mRNA expression significantly increased with age of kidney reaching a maximum at postnatal day 5 in both strains. Pappa2 mRNA expression at postnatal day 15 was found to be 9-fold higher in the kidney of 26-P compared with SS strain. Immunohistochemistry studies revealed that Pappa2 co-localized with IGFBP-5 in the ureteric bud indicating that Pappa2 could be important for ureteric branching and nephron endowment. Glomerulus/mm 2 was therefore determined by counting total number of glomeruli in kidney sections from pups starting from P0 to P20. The salt-resistant 26-P congenic strain exhibited significantly greater nephron density 9.03 and 7.07 glo/mm 2 compared to 6.89 and 4.85 glo/mm 2 in SS rat at day P15 and P20, respectively. It appears that the Brown Norway pappa2 allele variant prevents the reduced nephron numbers observed in SS rats and thereby protects these congenic rats from salt-induced hypertension.

Canine primary ciliary dyskinesis reveals a new gene involved in cilium structure and function

2010 ◽  
Vol 27 ◽  
pp. S8-S9
Author(s):  
A.C. Merveille ◽  
G. Battaille ◽  
E. Davis ◽  
F. Billen ◽  
C. Clercx ◽  
...  
Keyword(s):  
Structure And Function ◽  
New Gene ◽  
And Function

scholarly journals Tubuloglomerular Disease With Cone-Shaped Epiphyses Associated With Hypomorphic Variant and a Novel p.Cys14Arg in the TTC21B Gene: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Martin Bezdíčka ◽  
Dana Zemková ◽  
Sylva Skálová ◽  
Eva Hovorková ◽  
Miroslav Podhola ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Development ◽  
Kidney Biopsy ◽  
Intraflagellar Transport ◽  
X Ray ◽  
Heterozygous Variant ◽  
Renal Tubular ◽  
Nephrotic Range Proteinuria ◽  
Generation Sequencing

Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.

Sign in / Sign up

Export Citation Format

Share Document