In the Anthropocene, which is marked by the human impact on the environment through immense development of modern technologies, the general style and habits of people’s life are also altered accord...

Key Points: Inflammation and immune response pathways were enriched in IgA nephropathy/IgA vasculitis with nephropathy compared with living donors. The transcriptomic profile differed significantly between adults and children with the disease. Background: Disease manifestations and progression of IgA nephropathy vary widely between individuals, particularly between children and adults. To further understand these differences, we examined the transcriptional profiles in kidney biopsies from both adult and pediatric patients with IgA nephropathy or IgA vasculitis with nephropathy in relation to normal kidneys. Methods: Kidney biopsies from 95 participants, 71 adults and 13 children with histopathologically verified IgA nephropathy or IgA vasculitis with nephropathy as well as 11 living donors, were microdissected into glomerular and tubulointerstitial fractions and subjected to RNA sequencing. Differential gene expression analysis was performed across groups, and functional enrichment analyses were conducted using gene ontology and Kyoto Encyclopedia of Genes and Genomes. Histopathological grading (Oxford and part of the Banff classifications) and clinical data (at time of biopsy and up to 5 years of follow-up) were analyzed in relation to normalized RNA counts. Results: Differentially expressed genes obtained from all patients versus living donors, both glomerular and tubulointerstitial fractions, were enriched for immune system and complement activation pathways. When comparing adults with children within the IgA nephropathy/IgA vasculitis with nephropathy group, 5562 and 3539 differentially expressed genes in each fraction were identified, which were enriched in pathways related to the endoplasmic reticulum and mitochondrial activity (glomeruli), as well as T-cell activation (tubulointerstitium). Conclusions: Distinct transcriptional profiles with enrichment of inflammation and immune response pathways were revealed in patients compared with living donors. However, the transcriptomic signatures across adult and pediatric patients were not consistent, highlighting differences in pathways involved in endoplasmic reticular, mitochondrial, and T-cell activity. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2025_09_10_ASN0000000787.mp3

Patients with chronic kidney disease (CKD) face an increased risk of early vascular aging, progressive vascular calcification, and premature death. With increasing age, mitochondrial function and mitochondrial DNA copy number (mtDNA-cn) decline. This has been identified as an independent predictor of frailty and mortality in cardiovascular diseases (CVDs) and cancer. However, the relationship between mtDNA-cn and vascular calcification in the context of a uremic milieu remains ambiguous. We hypothesize that a lower mtDNA-cn is associated with medial calcification, as both are linked to impaired vascular health and accelerated aging. mtDNA-cn was analyzed in 211 CKD5 patients undergoing renal transplantation (RTx) and 196 healthy controls using quantitative PCR (qPCR) for three mtDNA genes (mtND1, mtND4, and mtCOX1) and single-locus nuclear gene hemoglobin beta (HbB). In 32 patients, mtDNA-cn was also quantified one year after RTx. The association between mtDNA-cn and vascular calcification scores, circulatory cell-free (ccf) mtDNA in plasma, and the surrogate marker of biological aging (skin autofluorescence) and CVD risk was assessed. mtDNA-cn was significantly lower in CKD5 patients than in controls and correlated with biological age, vascular calcification, and CVD risk. One year after RTx there was a significant recovery of mtDNA-cn in male patients compared to baseline levels. mtDNA-cn and ccf-mtDNA were inversely correlated. This prospective study provides novel insights into the link between low mtDNA-cn and vascular aging. It demonstrates that RTx restores mtDNA levels and may improve oxidative phosphorylation capacity in CKD. Further investigation is warranted to evaluate mtDNA as a biologically relevant biomarker and a potential therapeutic target for early vascular aging in the uremic environment.

Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood–brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to IS 200 and 900 μM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-β-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-β-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 µM and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 µM, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies.