Role of ultrastructural determinants of glomerular permeability in ultrafiltration function loss

Increased glomerular permeability to proteins is a characteristic feature of diabetic nephropathy (DN). The slit diaphragm is the major restriction site to protein filtration, and the loss of nephrin, a key component of the slit diaphragm, has been demonstrated in both human and experimental DN. Both systemic and glomerular hypertension are believed to be important in the pathogenesis of DN. Human immortalized podocytes were subjected to repeated stretch-relaxation cycles by mechanical deformation with the use of a stress unit (10% elongation, 60 cycles/min) in the presence or absence of candesartan (1 μM), PD-123319 (1 μM), and rosiglitazone (0.1 μM). Nephrin mRNA and protein expression were assessed using quantitative real-time PCR, immunoblotting, and immunofluorescence, and the protein expression of AT1 receptor and angiotensin II secretion were evaluated. Exposure to stretch induced a significant ∼50% decrease in both nephrin mRNA and protein expression. This effect was mediated by an angiotensin II-AT1 mechanism. Indeed, podocyte stretching induced both angiotensin II secretion and AT1 receptor overexpression, podocyte exposure to angiotensin II reduced nephrin protein expression, and both the AT-1 receptor antagonist candesartan and a specific anti-angiotensin II antibody completely abolished stretch-induced nephrin downregulation. Similar to candesartan, the peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, also inhibited stretch-induced nephrin downregulation, suggesting interference with stretch-induced activation of the angiotensin II-AT1 receptor system. Accordingly, rosiglitazone did not alter stretch-induced angiotensin II secretion, but it prevented AT1 upregulation in response to stretch. These results suggest a role for hemodynamic stress in loss of nephrin expression and allude to a role of PPAR-γ agonists in the prevention of this loss.

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Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier

AJP Renal Physiology ◽

10.1152/ajprenal.00131.2007 ◽

2007 ◽

Vol 293 (2) ◽

pp. F501-F505 ◽

Cited By ~ 22

Author(s):

Jan Michael Williams ◽

Mukut Sharma ◽

Siddam Anjaiahh ◽

John R. Falck ◽

Richard J. Roman

Keyword(s):

Arachidonic Acid ◽

Essential Role ◽

Dienoic Acid ◽

Permeability Barrier ◽

Selective Inhibitors ◽

Glomerular Permeability ◽

Isolated Glomeruli ◽

Cytochrome P 450 ◽

Protein Permeability

This study examined the metabolism of arachidonic acid (AA) by cytochrome P-450 enzymes in isolated glomeruli and the effects of selective inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatetraenoic acids (EETs) on glomerular permeability to albumin ( Palb). Glomeruli avidly produced 20-HETE, EETs, dihydroxyeicosatetraenoic acids (diHETEs), and HETEs when incubated with exogenous AA. N-hydroxy- N′-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 μM) selectively inhibited the formation of 20-HETE by 95% and increased Palb from 0.00 ± 0.08 to 0.73 ± 0.10 ( n = 43 glomeruli, 4 rats). Addition of a 20-HETE mimetic, 20-hydroxyeicosa-5( Z),14( Z)-dienoic acid (20-5,14-HEDE; 1 μM) opposed the effects of HET0016 (10 μM) to increase Palb (0.21 ± 0.10, n = 36 glomeruli, 4 rats). Preincubation of glomeruli with exogenous AA to increase basal production of 20-HETE had a similar effect. We also examined the effect of an epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 μM), on Palb. MSPPOH (5 μM) significantly increased Palb but had no effect on the synthesis of EETs in glomeruli incubated with AA. However, MSPPOH (5 μM) selectively reduced epoxygenase activity by 50% in glomeruli incubated without added AA. Pretreatment with 8,9-EET (100 nM) attenuated the effects of MSPPOH (5 μM) on Palb. These results indicate that glomeruli produce 20-HETE, EETs, diHETEs, and HETEs and that endogenously formed 20-HETE and EETs play an essential role in the maintenance of the glomerular permeability barrier to albumin.

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Radiation-Induced Brachial Plexopathy in Breast Cancer and the Role of Surgical Treatment

Indian Journal of Neurosurgery ◽

10.1055/s-0040-1712272 ◽

2020 ◽

Vol 9 (02) ◽

pp. 099-105

Author(s):

Kenan Kıbıcı ◽

Berrin Erok ◽

Ali Önder Atca

Keyword(s):

Breast Cancer ◽

Brachial Plexopathy ◽

Breast Cancer Patients ◽

Function Loss ◽

Radiation Induced ◽

The Mean ◽

Grade 3 ◽

Surgical Treatments ◽

Experienced Grade

Abstract Objective We aimed to evaluate improvement in the pain, motor, and sensory functions after neurosurgical intervention, by objective methods in patients with radiation-induced brachial plexopathy (RIBP), as a complication of radiotherapy (RT). Materials and Methods In our study, 11 patients, who experienced grade 3 or 4 brachial plexopathy according to the LENT-SOMA (late effects of normal tissue—subjective, objective, management, analytic) side-effect index, as a complication of RT which was performed after being operated for breast cancer, were included. In the postoperative period pain, sensation, and motor function loss were followed. Results There was apparent regression in the pain. The mean visual analogue scale (VAS) value decreased to 4 from the preoperative VAS value of 9.4. However, no significant improvement was observed in either sensory and motor functions. Conclusion RIBP is a progressive disease in breast cancer patients after radiotherapy. Evaluation of the results of applied surgical treatments and changes in the results with time is important to direct the treatment. Neurolysis should only be considered when other treatment methods fail and should be considered as an irreversible and potentially permanent procedure.

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Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

Clinical Science ◽

10.1042/cs20040095 ◽

2004 ◽

Vol 107 (2) ◽

pp. 125-136 ◽

Cited By ~ 79

Author(s):

José G. van den BERG ◽

Jan J. WEENING

Keyword(s):

Nephrotic Syndrome ◽

Immune System ◽

Direct Evidence ◽

Idiopathic Nephrotic Syndrome ◽

Minimal Change ◽

Focal And Segmental Glomerulosclerosis ◽

Glomerular Permeability ◽

Glomerular Capillary ◽

Glomerular Barrier

Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in the glomerular barrier to proteins. Genetic defects that affect the function and the composition of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been recognized as the cause of familial forms of NS. MCNS (minimal change NS) and FSGS (focal and segmental glomerulosclerosis) are common non-familial forms of NS in which the causative defect has not yet been identified. Several studies have shown that non-familial NS is associated with the presence of circulating permeability factors and with complex disturbances in the immune system. Thus far, there is no direct evidence that these factors directly alter glomerular permeability to proteins, and some of these factors may be a consequence, rather than a cause, of NS. In this review, we will briefly highlight the mechanisms that underlie proteinuria in general and focus on the immunological disturbances associated with idiopathic NS, with attention to potential mechanisms whereby the immune system may directly act on the glomerular capillary filter.

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Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates

European Journal of Human Genetics ◽

10.1038/s41431-021-00850-9 ◽

2021 ◽

Author(s):

Beatrice Spedicati ◽

Massimiliano Cocca ◽

Roberto Palmisano ◽

Flavio Faletra ◽

Caterina Barbieri ◽

...

Keyword(s):

Signs And Symptoms ◽

Loss Of Function ◽

Delayed Treatment ◽

Mendelian Disorders ◽

Naturally Occurring ◽

Function Loss ◽

Genetic Isolates ◽

Autosomal Recessive Diseases ◽

Deep Phenotyping

AbstractWhole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants tend to be significantly enriched in “genetic isolates,” making these populations specifically suited for HKO studies. In this work, a meticulous WGS data analysis combined with an in-depth phenotypic assessment of 947 individuals from three Italian genetic isolates led to the identification of ten biallelic LoF variants in ten OMIM genes associated with known autosomal recessive diseases. Notably, only a minority of the identified HKOs (C7, F12, and GPR68 genes) displayed the expected phenotype. For most of the genes, instead, (ACADSB, FANCL, GRK1, LGI4, MPO, PGAM2, and RP1L1), the carriers showed none or few of the signs and symptoms typically associated with the related diseases. Of particular interest is a case presenting with a FANCL biallelic LoF variant and a positive diepoxybutane test but lacking a full Fanconi anemia phenotypic spectrum. Identifying KO subjects displaying expected phenotypes suggests that the lack of correct genetic diagnoses may lead to inappropriate and delayed treatment. In contrast, the presence of HKOs with phenotypes deviating from the expected patterns underlines how LoF variants may be responsible for broader phenotypic spectra. Overall, these results highlight the importance of in-depth phenotypical characterization to understand the role of LoF variants and the advantage of studying these variants in genetic isolates.

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Circular RNA CREBBP Suppresses Hepatic Fibrosis Via Targeting the hsa-miR-1291/LEFTY2 Axis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.741151 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ya-Ru Yang ◽

Shuang Hu ◽

Fang-Tian Bu ◽

Hao Li ◽

Cheng Huang ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Circular Rna ◽

Vehicle Group ◽

Potential Biomarker ◽

Function Loss ◽

And Function ◽

Pro Inflammatory Cytokines

CircRNAs (circRNAs) are commonly dysregulated in a variety of human diseases and are involved in the development and progression of cancer. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous high throughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl4)-induced HF. For example, circCREBBP was significantly down-regulated in primary hepatic stellate cells (HSCs) and liver tissue of HF mice induced by CCl4 compared to those in the vehicle group. Overexpression of circCREBBP with AAV8-circCREBBP in vivo prevented CCl4-induced HF worsening by reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) contents, liver hydroxyproline levels, collagen deposition, and levels of pro-fibrosis genes and pro-inflammatory cytokines. Furthermore, in vitro function loss and function gain analysis showed that circCREBBP inhibited HSCs activation and proliferation. Mechanically, circCREBBP acts as a sponge for hsa-miR-1291 and subsequently promotes LEFTY2 expression. In conclusion, our current results reveal a novel mechanism by which circCREBBP alleviates liver fibrosis by targeting the hsa-miR-1291/LEFTY2 axis, and also suggest that circCREBBP may be a potential biomarker for heart failure.

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Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p

Open Medicine ◽

10.1515/med-2021-0319 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1378-1385

Author(s):

Chen-Min Sun ◽

Wen-Yi Zhang ◽

Shu-Yan Wang ◽

Gang Qian ◽

Dong-Liang Pei ◽

...

Keyword(s):

Renal Fibrosis ◽

Target Gene ◽

Rat Kidney ◽

Inflammatory Factors ◽

Strongly Correlated ◽

Tnf Α ◽

Function Loss

Abstract Aim Renal fibrosis (RF) is a common clinical condition leading to irreversible renal function loss. Tyrosine kinase proteins and microRNAs (miRs) are associated with pathogenesis and we aim to investigate the role of Fer and its partner miR(s) in RF. Method In silico reproduction of Mouse Kidney FibrOmics browser was performed to identify potential miR(s) and target gene(s). In vivo validation was performed in C57BL/6 mice with unilateral ureteral obstruction (UUO). In vitro validation was performed in rat kidney fibroblast NRK-49F cells. Mimics and inhibitors of miR-29c-3p were constructed. The target gene Fer was monitored by RT-PCR and western blotting. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in serum and media were measured by ELISA. Results The Fer expression and protein level were gradually increased during 14 days of UUO modeling. miR-29c-3p expression was strongly correlated with that of Fer. In vivo validation showed increased expressions of fibrosis-associated genes and increased phospoho-Smad3 level in the UUO model. Fer-knockdown (KD) significantly decreased expressions of fibrosis-associated genes. Pharmaceutical inhibition of Fer showed similar effects to miR-29c-3p, and miR inhibition showed a significant decrease of excretion of inflammatory factors. Conclusion Dysregulation of miR-29c-3p and Fer plays a role in RF. Pharmaceutical or genetic inhibition of Fer may serve as the potential treatment for RF.

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Role OF Na+ transporters HKT1;1 and HKT1;2 in tomato salt tolerance. I. function loss of cheesmaniae alleles in rootsand aerial parts

Plant Physiology and Biochemistry ◽

10.1016/j.plaphy.2021.10.018 ◽

2021 ◽

Author(s):

María Remedios Romero-Aranda ◽

Jesús Espinosa ◽

Paloma González-Fernández ◽

Emilio Jaime-Fernández ◽

José Ángel Traverso ◽

...

Keyword(s):

Salt Tolerance ◽

Aerial Parts ◽

Function Loss

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The endoplasmic reticulum protein SEC22B interacts with NBEAL2 and is required for megakaryocyte α-granule biogenesis

Blood ◽

10.1182/blood.2019004276 ◽

2020 ◽

Vol 136 (6) ◽

pp. 715-725 ◽

Cited By ~ 1

Author(s):

Richard W. Lo ◽

Ling Li ◽

Fred G. Pluthero ◽

Richard Leung ◽

Koji Eto ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Dynamic Network ◽

Hek293 Cells ◽

Loss Of Function ◽

Function Loss ◽

Endoplasmic Reticulum Protein ◽

Gray Platelet Syndrome ◽

Endogenous Proteins ◽

And Function

Abstract Studies of inherited platelet disorders have provided many insights into platelet development and function. Loss of function of neurobeachin-like 2 (NBEAL2) causes gray platelet syndrome (GPS), where the absence of platelet α-granules indicates NBEAL2 is required for their production by precursor megakaryocytes. The endoplasmic reticulum is a dynamic network that interacts with numerous intracellular vesicles and organelles and plays key roles in their development. The megakaryocyte endoplasmic reticulum is extensive, and in this study we investigated its role in the biogenesis of α-granules by focusing on the membrane-resident trafficking protein SEC22B. Coimmunoprecipitation (co-IP) experiments using tagged proteins expressed in human HEK293 and megakaryocytic immortalized megakaryocyte progenitor (imMKCL) cells established binding of NBEAL2 with SEC22B, and demonstrated that NBEAL2 can simultaneously bind SEC22B and P-selectin. NBEAL2-SEC22B binding was also observed for endogenous proteins in human megakaryocytes using co-IP, and immunofluorescence microscopy detected substantial overlap. SEC22B binding was localized to a region of NBEAL2 spanning amino acids 1798 to 1903, where 2 GPS-associated missense variants have been reported: E1833K and R1839C. NBEAL2 containing either variant did not bind SEC22B coexpressed in HEK293 cells. CRISPR/Cas9-mediated knockout of SEC22B in imMKCL cells resulted in decreased NBEAL2, but not vice versa. Loss of either SEC22B or NBEAL2 expression resulted in failure of α-granule production and reduced granule proteins in imMKCL cells. We conclude that SEC22B is required for α-granule biogenesis in megakaryocytes, and that interactions with SEC22B and P-selectin facilitate the essential role of NBEAL2 in granule development and cargo stability.

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Activation of the CRF 2 receptor modulates skeletal muscle mass under physiological and pathological conditions

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00081.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E889-E898 ◽

Cited By ~ 17

Author(s):

Richard T. Hinkle ◽

Elizabeth Donnelly ◽

David B. Cody ◽

Steven Samuelsson ◽

Jana S. Lange ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Nerve Damage ◽

Skeletal Muscle Atrophy ◽

Function Loss ◽

Selective Agonists ◽

And Function ◽

First Time

Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRF1R) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass.

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