Endoplasmic Reticulum Stress Mediates Renal Tubular Vacuolation in BK Polyomavirus-Associated Nephropathy

Abstract

ObjectiveThis study aimed to explore the molecular mechanism of cytoplasmic vacuolation caused by BK polyomavirus (BKPyV) and thus search for potential target for drug repurposing.MethodsMorphological features of BK polyomavirus-associated nephropathy (BKPyVAN) were studied under light and electron microscopes. Microarray datasets GSE75693, GSE47199, and GSE72925 were integrated by ComBat, and differentially expressed genes (DEGs) were analyzed using limma. Furthermore, the endoplasmic reticulum (ER)-related genes obtained from GenCLiP 2.0 were intersected with DEGs. GO and KEGG enrichment pathways were performed with intersection genes by R package clusterProfiler. The single-cell RNA sequencing (scRNA-seq) from a BKPyVAN recipient was analyzed with a dataset (GSE140989) downloaded from Gene Expression Omnibus (GEO) as control for gene set variation analysis (GSVA). Immunohistochemistry and electron microscopy of kidney sections from drug-induced ERS mouse models were performed to explore the association of ERS and renal tubular vacuolation. Protein–protein interaction (PPI) network of the intersection genes was constructed to identify hub target. AutoDock was used to screen Food and Drug Administration (FDA)-approved drugs that potentially targeted hub gene.ResultsLight and electron microscopes exhibited obvious intranuclear inclusions, vacuoles, and virus particles in BKPyV-infected renal tubular cells. Transcriptome analysis revealed 629 DEGs between samples of BKPyVAN and stable transplanted kidneys, of which 16 were ER-associated genes. GO analysis with the intersection genes illustrated that ERS-related pathways were significantly involved, and KEGG analysis showed a prominent enrichment of MAPK, Toll-like receptor, and chemokine signaling pathways. GSVA analysis of the proximal tubule revealed similar pathways enrichment. An electron microscope image of the kidney from ERS mouse models showed an obvious renal tubular vacuolation with prominent activation of ERS markers verified by immunohistochemistry. Furthermore, DDIT3 was identified as the hub gene based on PPI analysis, and ZINCOOOOO1531009 (Risedronate) was indicated to be a potential drug for DDIT3.ConclusionERS was involved in renal tubular cytoplasmic vacuolation in BKPyVAN recipients. Risedronate was screened as a potential drug for BKPyVAN by targeting DDIT3.

Human genes with relative synonymous codon usage analogous to that of polyomaviruses are involved in the mechanism of polyomavirus nephropathy

“…HPyV T Antigen has been also reported to regulate the APOBEC3B ( Starrett et al., 2019 ). Pathological and bioinformatics analyses indicated that genes regulated by BK HPyV infection are involved in cytoplasmic vacuolation implicating endoplasmic reticulum stress with DDIT3 as the key hub gene ( Zhao et al., 2022 ). The analysis of BK PVAN transcriptome was unable to uncover BK PVAN-specific molecular signatures, which limits the clinical application of the corresponding findings ( Pan et al., 2018 ).…”

Seasonal changes in endoplasmic reticulum stress and ovarian steroidogenesis in the muskrats (Ondatra zibethicus)

“…The endoplasmic reticulum (ER) is the primary cell organ accountable for various particular cellular processes such as the synthesis and folding of secretory or membrane proteins, fatty acid and steroid biosynthesis, and Ca 2+ storage ( 1 , 2 ). Endoplasmic reticulum stress (ERS) is induced when there is an imbalance between the volume in the ER and the protein folding load, it causes a buildup of unfolded or improperly folded proteins ( 3 ). Numerous physiological and pathological processes, including excessive secretion requirement, damaged calcium homeostasis, changed lipid homeostasis, oxidative stress, and production of the mutant protein linked to disease all contribute to the induction of ERS ( 4 – 7 ).…”