Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment

Wang, Juan; Hidaka, Teruo; Sasaki, Yu; Tanaka, Eriko; Takagi, Miyuki; Shibata, Terumi; Kubo, Ayano; Trejo, Juan Alejandro Oliva; Wang, Lining; Asanuma, Katsuhiko; Tomino, Yasuhiko

doi:10.1038/s41598-018-35465-6

Cited by 6 publications

(6 citation statements)

References 32 publications

(34 reference statements)

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“…In addition, we found a number of genes, including podocin (Nphs2), Synpo, and nephrin (Nphs1), that participate in the maintenance of the glomerular filtration barrier to be significantly decreased in obese SS LepR mutant compared with lean SS WT rats. Dysfunction or reduction of these genes has been shown to contribute to progressive albuminuria and renal injury (7,52,54,63,(77)(78)(79)91). The only gene that we found to be markedly increased was Trpc6; a gain in function of Trpc6 has been associated with focal segmental glomerulosclerosis (20,29,61,87,92).…”

Section: Discussionmentioning

confidence: 65%

Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats

McPherson

Shields

Poudel

et al. 2020

American Journal of Physiology-Renal Physiology

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The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 ( Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.

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Section: Discussionmentioning

confidence: 65%

Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats

McPherson

Shields

Poudel

et al. 2020

American Journal of Physiology-Renal Physiology

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“…We hypothesised that the protective effect of TB4 in ADR injury may be partly mediated by its ability to sequester G-actin and regulate F-actin polymerisation 13 , 14 , 46 . Using synaptopodin as a podocyte marker 47 , and phalloidin to visualise F-actin filaments, we quantified F-actin in the synaptopodin-positive regions (Fig. 4 f).…”

Section: Resultsmentioning

confidence: 99%

Systemic gene therapy with thymosin β4 alleviates glomerular injury in mice

Mason

Jafree

Pomeranz

et al. 2022

Sci Rep

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Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease.

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“…With the increasing use of blood assays, variables such as exercise ( Joisten et al, 2021 ), blood volume, body mass index need to be considered ( Manouchehrinia et al, 2020 ; Perino et al, 2021 ). Trace amounts of NfPs relative to those in neurons have been reported in erythrocytes ( Granger and Lazarides, 1983 ; Terasawa et al, 2006 ), T lymphocytes ( Murphy et al, 1993 ), podocytes ( Wang et al, 2018 ), and oocytes ( Takahashi and Ishizuka, 2012 ), which could be confounds in certain disease conditions. Because blood NfL alteration is associated with aging, future studies are also needed to establish the age-adjusted normal values of serum NfL levels across all age groups.…”

Section: Current Research Gaps and Potential Development Of Neurofilaments As Biomarkersmentioning

confidence: 99%

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

2021

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Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

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Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment

Cited by 6 publications

References 32 publications

Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats

Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats

Systemic gene therapy with thymosin β4 alleviates glomerular injury in mice

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

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