bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.06.11.448004

Stx2 Induces Differential Gene Expression by Activating Several Pathways and Disturbs Circadian Rhythm Genes in the Proximal Tubule.

Obata, F.·Ozuru, R.·Tsuji, T.·Matsuba, T.·Fujii, J.
View original source ↗Export metadata ↓

Abstract

(1) BackgroundShiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. (2) MethodsWe determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected, and microarray analysis was performed. (3) ResultsWe compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control (0 h, no toxin-treated). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1(SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. (4) ConclusionsStx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance resulting in proximal tubular dysfunctions.

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Obata, F., Ozuru, R., Tsuji, T., Matsuba, T., Fujii, J.. 2021-06-11. Stx2 Induces Differential Gene Expression by Activating Several Pathways and Disturbs Circadian Rhythm Genes in the Proximal Tubule.. https://doi.org/10.1101/2021.06.11.448004

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

sPLA2 inhibitor-loaded nanoparticles mitigate spontaneous osteoarthritis in guinea pigs

Osteoarthritis (OA) is a prevalent degenerative joint disease lacking effective disease-modifying therapies. Secreted phospholipase A2 (sPLA2), a key upstream regulator of inflammatory lipid mediators, has been implicated in OA pathogenesis, but its therapeutic potential in age-related OA remains unclear. Here, we evaluated the role of sPLA2 and the efficacy of nanoparticle-mediated sPLA2 inhibition in a spontaneous OA model using female Dunkin-Hartley (DH) guinea pigs. We first characterized OA progression and observed age-dependent increases in cartilage degeneration, synovitis, oxidative stress, and sPLA2 expression and enzymatic activity. We then developed sPLA2 inhibitor (thioetheramide-PC)-loaded nanoparticles (sPLA2i-NPs) and demonstrated their superior ability, compared to free inhibitor, to prevent IL-1{beta}-induced cartilage degeneration in guinea pig cartilage explants. In vivo, intra-articular administration of sPLA2i-NPs from 3 months of age significantly attenuated cartilage destruction, synovial inflammation, and osteophyte formation in 7- and 10-month-old guinea pigs. These structural improvements were accompanied by normalization of anabolic and catabolic gene expression and a marked reduction in synovial fluid sPLA2 activity. Importantly, longitudinal gait analysis revealed that sPLA2i-NP treatment preserved limb loading, propulsion, and locomotor performance, demonstrating functional recovery. No systemic toxicity was observed following long-term treatment. Collectively, our findings identify sPLA2 as a key driver of spontaneous OA and establish nanoparticle-mediated sPLA2 inhibition as a promising disease-modifying strategy for age-related OA.

pathology↗
bioRxiv2026

Midlife nonlinearities across scale in Biondi body amyloid formation in the human choroid plexus

Human choroid plexus epithelial cells (CPECs), which produce cerebrospinal fluid and form the blood-cerebrospinal fluid barrier, accumulate discrete intracellular amyloid inclusions called Biondi bodies (BBs). Using systematic manual and machine learning approaches on the choroid plexus glomus, we determined the percentages of CPECs containing thioflavin S-stained BBs as well as BB load and spatial distributions in whole slide images from 77 cases across the human lifespan. On average, BB prevalence was near zero until age 40, rose steeply in the 5th and 6th decades, and exceeded 50% after age 70. As prevalence plateaued, BB load continued to rise with age. Accelerated BB accumulation was seen in two cases of diabetic ketoacidosis, including a 16-year-old, while an 85-year-old with the relatively rare APOE2/E2 genotype had fewer BBs than expected. BB prevalence in the choroid plexus glomus was not associated with Alzheimer's disease, but was lower in females than males. Notably, spatial clustering of BBs was universal across cases while nearest-neighbor analyses suggested cell-to-cell, prion-like BB spread that can account for the nonlinearities seen at tissue and population scales. The abrupt, nonlinear BB accumulation during midlife coincides with or precedes other common aging-associated neuropathologies of the human brain, consistent with broad BB and choroid plexus contributions to brain aging and disease.

pathology↗
bioRxiv2026

Elevated precontractile calcium set point is sustained by limited PMCA1 export in dystrophic muscle

Duchenne muscular dystrophy is caused by loss of dystrophin and marked by elevated muscle calcium, usually attributed to contraction-induced membrane damage. Whether calcium rises before muscle can contract, and what sustains it, is unresolved. In Caenorhabditis elegans embryos and patient-derived human myoblasts, dystrophic muscle carries an elevated resting calcium set point before contraction is possible. Embryonic calcium is elevated 400 minutes after fertilization, before movement is detectable or the neuromuscular junction forms. Silencing the plasma membrane calcium pump gene mca-1 raises calcium in wild-type but not dystrophic animals, whereas silencing its paralogue raises it in both: the limitation is specific to that export route. Dystrophic human myoblasts have less pump; pump inhibition or silencing increases calcium preferentially in healthy cells, and raising pump expression lowers calcium most in dystrophic cells. Constrained calcium export is an early, continuing determinant of the dystrophic set point.

pathology↗