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Integrated bulk and spatial transcriptomic analysis identifies progression-associated molecular signatures in biopsy-proven hypertensive nephropathy [NanoString]

ABSTRACT: Hypertensive nephropathy (HN) is a leading cause of chronic kidney disease (CKD), but molecular mechanisms underlying disease progression remain poorly understood. We aimed to identify transcriptomic signatures associated with disease progression and to localize these signatures within renal architectures. Patients with biopsy-proven HN were selected from the Norwegian Kidney Biopsy Registry and stratified after ≥5 years of follow-up into early stable (ES), early progressor (EP), late stable (LS) and late progressor (LP) based on baseline kidney function and annual eGFR decline. Bulk transcriptomic profiling was performed in a discovery cohort and validated in an independent cohort using nCounter profiling. Spatial transcriptomics was applied to map progression-associated signatures to nephron compartments. Bulk RNA sequencing identified 415 differentially expressed genes (DEGs) between ES and EP, and 692 between LS and LP samples. ES was enriched in circadian rhythm pathways, with reduced NR1D1 and NR1D2 expression in EP. LP was associated with metabolic reprogramming including glutathione, retinol and amino acid metabolism. Random forest modelling identified NR1D1 gene expression as a key classifier, validated in an independent cohort. Spatial transcriptomics revealed nephron segment-specific expression patterns, including a proximal tubule cluster enriched in ferroptosis in LP. Comparative nephron-segment analyses across groups revealed progression-associated biomarkers, including CHGA, CCN2 and SFRP2 in glomeruli, and APOE in proximal tubules. HN progression appears to involve stage-specific and compartmentalized molecular programs. Integration of bulk and spatial transcriptomics identifies candidate biomarkers and pathways, potentially supporting innovative prognostic stratification and therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339454 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Introduction: Low birthweight is a risk factor for chronic kidney disease (CKD), in part due to an associated low nephron number, but the mechanisms leading to increased risk are not well understood. Low birthweight and growth restriction can be modeled in mice using gestational low protein (LP). Using this model, here we sought to 1) identify a potential window for therapeutic intervention to prevent future CKD in LP animals, 2) understand the transcriptional impact of LP on adult kidneys, and 3) clarify the mechanistic connection between low nephron endowment and predisposition to disease in LP animals. We hypothesized that gestational LP-induced growth restriction would lead to shorter nephrogenesis and altered gene expression in adulthood. Methods: At the initiation of pregnancy, CD-1 dams received a normal protein (NP, 18%) or LP (8%) diet. Offspring were euthanized on postnatal days (PN) 2-7 (n=2-7/day). Kidneys were stained with Periodic acid–Schiff (PAS). Immunofluorescence was used to assess SIX2 (progenitor cells), JAG1 (nascent nephron patterning), and LEF1 (Wnt signaling). At 6 weeks, mice underwent transdermal glomerular filtration rate (GFR) measurement. Ex vivo kidneys underwent histologic evaluation, bulk RNA sequencing, and cationic ferritin- enhanced MRI to quantify glomerular number (Nglom). Results: LP mice had protracted nephrogenesis extending to PN5-6, compared to NP mice that had completed nephrogenesis by PN3-5. Adult LP mice had fewer glomeruli, and LP males had lower GFR and more ATG compared to NP males. LP mice did not have evidence of glomerular hypertrophy. In LP males, the following genes were downregulated: Gfr1, Pax8, Fgf10, Dvl1, and Aldh1a1. Foxd1, Hif1an, Egln3, and Fzd7 were upregulated in the LP males. LP females exhibited upregulation of Etv5 and Osr2 and downregulation of Gata3, Mgp, and Trpv6 with no overlap of dysregulated genes between the sexes. Conclusions: LP offspring exhibit prolonged nephrogenesis and a reduced nephron endowment in adulthood. In males, this is characterized by a suppressed retinoic acid–GDNF–Wnt axis, while both sexes show persistent dysregulation of developmental genes. Together, these findings identify the late gestational and early postnatal periods as critical therapeutic windows. Targeting these molecular pathways during active nephrogenesis may offer a strategy to mitigate the programmed risk of CKD in growth-restricted offspring.

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Integrated bulk and spatial transcriptomic analysis identifies progression-associated molecular signatures in biopsy-proven hypertensive nephropathy [NanoString]

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