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Methylseq, Single-nuclei RNAseq, and Discovery Proteomics Identifies Pathways Associated with Nephron Deficit CKD in the HSRA Rat Model [scRNA-Seq]

ABSTRACT: Low nephron numbers are associated with increased risk of developing chronic kidney disease (CKD) and hypertension, both significant global health problems. To investigate the impact of nephron deficiency, our lab developed a novel inbred rat model (HSRA rat). In this model, approximately 75% of offspring are born with a single kidney (HSRA-S), compared to two-kidney littermates (HSRA-C). HSRA-S rats show impaired kidney development, resulting in ~20% fewer nephrons. Our previous data and current findings demonstrate nephron deficit (failure of one kidney to form and altered development in the remaining kidney) predispose HSRA-S to CKD late in life (increased proteinuria by 18 months of age in HSRA-S=51± 3.4 versus HSRA-C = 8± 1.5 mg/24hours). To understand early molecular mechanisms contributing to the increased predisposition to CKD, Methylseq using reduced representation bisulfite sequencing, single nuclei (sn)RNAseq, and discovery proteomics were performed in kidneys of 4-week-old HSRA rats. Methylation analysis revealed a small number of differences, including 5 differentially methylated cytosines and 6 differentially methylated regions between groups. The snRNAseq analysis identified differentially expressed genes in most kidney cell types, with several hundred genes dysregulated depending on the analysis method (Seurat vs DESeq2). Notably, many genes are involved in kidney development. Discovery proteomic analysis identified 366 differentially expressed proteins. A key finding was dysregulation of Deptor/DEPTOR and Amdhd2/AMDHD2 across omics layers, suggesting a potential role in compensatory mechanisms or the genetic basis of altered kidney development. Further understanding of these mechanisms may guide interventions to preserve nephron health and slow kidney disease progression.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE289104 | GEO | 2025/07/09

REPOSITORIES: GEO

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Project description:Preterm neonates are at high risk for nephron loss under adverse clinical conditions (e.g., cardiocirculatory decompensation, nephrotoxic drugs). Importantly, the onset of renal damage potentially collides with the proceeding nephrogenesis of prematurity prior 36 weeks of gestation. Recent animal studies suggest that early nephron loss within this vulnerable phase is associated with more severe glomerular and tubulointerstitial alterations later in life, irrespective of the occurrence of arterial hypertension. It is known that nephrogenic pathways are reactivated after acute kidney injury supporting renal repair and regeneration. In this study we hypothesized that nephron loss during nephrogenesis leads to an alteration of the kidney developmental program which in turn impairs homeostasis and repair and thus aggravates kidney injury later in life. Preterm infants prior to 36 weeks of gestation show an active nephrogenesis after birth. In rats, nephrogenesis is still active until day 10 of life. Mimicking the human situation of acute nephron loss in preterm neonates with ongoing nephrogenesis, rats were uninephrectomized at day 1 of life (UNXd1). A second group of animals was uninephrectomized at day 14 of life (UNXd14), which resembles a nephron loss after terminated nephrogenesis. Age-matched control groups were sham operated. Three days after uninephrectomy the animals were sacrificed. Transcriptional renal changes were analyzed by RNAseqencing, followed by in silico functional pathway analysis. In UNXd1 animals 1182 genes were differentially regulated compared to the respective control group. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations in UNXd1 animals. Reduced expression levels of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and kidney injury (nephrin, podocin, Tgf-β1) were detected in the kidney of UNXd1 animals. The downregulation of Bmp7 and Gdnf expression in the remaining kidney of UNXd1 animals persisted until day 28 of life. In UNXd14 rats Six2 was upregulated and Pax22 downregulated compared to controls. We conclude that neonatal nephron loss during active nephrogenesis affects renal development and induces persistently reduced expression levels of genes which in turn might hinder tissue repair after kidney injury later in life.

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Methylseq, Single-nuclei RNAseq, and Discovery Proteomics Identifies Pathways Associated with Nephron Deficit CKD in the HSRA Rat Model [scRNA-Seq]

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