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May 14, 2026Physiology

Discovery of Molecular Pathways Underlying NOX4-Derived Oxidative Stress–Mediated Hypertension in Dahl Salt-Sensitive Rat

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Why the study?

Germline NOX4 knockout differences may reflect developmental compensation or strain adaptations rather than direct effects of NOX4-derived oxidative stress in salt-induced hypertension.

Population

SS, SD, and SSNOX4-/- rats

Comparison

0.4% low-salt vs 7 days 4.0% high-salt conditions across strains

Design

Reanalysis of RNA-seq and metabolomic datasets using TOST equivalence testing

Follow-up

7 days

Key result

A TOST-based analytical pipeline applied to rat kidney datasets identified protein turnover and nucleotide metabolic rewiring as uniquely altered pathways in hypertensive SS rats (p<0.05).

Authors

SSSatoshi ShimadaIVIbrahim VazirabadCYChun Yang

Discussion

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Overview

SS-specific transcript changes suggest direct NOX4 effects on salt hypertension; animal data leave open human relevance.

Key Points

  • The aim is to investigate how NOX4-derived oxidative stress contributes to hypertension in Dahl salt-sensitive rats by identifying relevant molecular pathways.
  • RNA-seq and metabolomic datasets analyzed from the kidneys of SS, SD, and SSNOX4-/- rats under low-salt and high-salt conditions.
  • TOST procedure used for equivalence assessment between salt responses, with parameters set for RNA-seq and metabolomics.
  • Pathway analysis conducted on significantly altered genes and metabolites to discern unique changes in hypertensive SS rats.
  • 2,556 genes in the cortex and 112 in the outer medulla were identified as equivalent under salt conditions.
  • KEGG pathway analysis revealed significant enrichment in autophagy, lysosome, and protein turnover pathways in the cortex, with p < 0.05 for statistical significance.
  • Integrated analysis found alterations in adenine and nucleic-acid turnover, indicating unique metabolic shifts in hypertensive SS rats.

Structured PICO

P
Population
Dahl salt-sensitive (SS) rats, salt-insensitive Sprague-Dawley (SD) rats, and SSNOX4-/- rats
I
Intervention
7 days of 4.0% high-salt (HS) diet compared to 0.4% low-salt (LS) diet
C
Comparator
Salt-resistant strains (SD and SSNOX4-/- rats) compared to salt-sensitive (SS) rats
O
Outcome
Transcriptomic (RNA-seq) and metabolomic changes in the kidney cortex and outer medullasurrogate

Main Result

p-value: p=<0.05

NOX4-derived oxidative stress in salt-sensitive hypertension is associated with specific alterations in protein turnover and nucleotide metabolism in the kidney cortex, rather than broad inflammatory pathways.

Cite This Study

Shimada et al. (2026) studied Salt-induced hypertension. 4.0% high-salt (HS) diet vs. 0.4% low-salt (LS) diet was evaluated on Genes significantly changed only in SS rats in the kidney cortex (Cx) (p=<0.05). A TOST-based analytical pipeline applied to rat kidney datasets identified protein turnover and nucleotide metabolic rewiring as uniquely altered pathways in hypertensive SS rats (p<0.05).

synapsesocial.com/papers/6a05685ca550a87e60a20ed2https://doi.org/10.1152/physiol.2026.41.s1.2297301
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