Key result
High-salt diet drives severe hypertension and alters ~81 renal genes unaffected by subdepressor imidapril.
Why the study?
The early molecular events linking excess salt exposure to kidney damage remain incompletely understood, and early metabolic and transcriptional remodeling in the Dahl salt-sensitive rat kidney has not been fully characterized.
Does subdepressor ACE inhibition with imidapril modify early high-salt-induced metabolic and extracellular matrix remodeling in the kidneys of Dahl salt-sensitive rats?
Does subdepressor ACE inhibition with imidapril modify early high-salt-induced metabolic and extracellular matrix remodeling in the kidneys of Dahl salt-sensitive rats?
High dietary salt induces early transcriptional extracellular matrix remodeling and mitochondrial metabolic dysfunction in the kidneys of Dahl salt-sensitive rats prior to overt histological fibrosis, and these early alterations are not attenuated by subdepressor ACE inhibition.
Subdepressor ACE inhibition fails to prevent high-salt kidney gene changes in Dahl rats; leaves open whether ACE inhibitors mitigate early renal remodeling in salt-sensitive models.
Excess salt is a major contributor to hypertension and hypertensive kidney injury, yet the early molecular events linking salt exposure to kidney damage remain incompletely understood. The Dahl salt-sensitive rat is a well-established model of salt-induced hypertension, but early metabolic and transcriptional remodeling in the kidney has not been fully characterized. We investigated early kidney alterations in 35 Dahl salt-sensitive rats fed a high-sodium (HSD) or low-sodium diet (LSD). A subgroup of HSD-fed rats received the ACE inhibitor imidapril at a subdepressor dose (1 mg/kg/day) to examine blood pressure-independent effects. Kidney tissue from 12-week-old animals was analyzed using histology, electron microscopy, transcriptomics, metabolomics, and angiotensin peptide profiling. HSD-fed rats developed hypertension by week 9 and showed kidney remodeling by week 12, including metabolic and transcriptional alterations suggestive of disrupted tricarboxylic acid cycle activity and impaired oxidative phosphorylation in the absence of overt fibrosis. Intra-kidney angiotensin I, II, and angiotensin 1–7 levels were reduced under HSD. Subdepressor ACE inhibition did not significantly alter blood pressure, kidney injury, angiotensin peptide levels, or the transcriptional and metabolic alterations observed in HSD-fed animals. These findings indicate that high salt intake induces early metabolic and extracellular matrix remodeling that is not modified by subdepressor ACE inhibition.
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Schüller et al. (2026) studied Salt-sensitive hypertension and early hypertensive kidney injury (Dahl salt-sensitive rat model) (n=35). High-salt diet (HSD) with or without subdepressor Imidapril (ACE inhibitor) vs. Low-salt diet (LSD, 0.3% NaCl) was evaluated on Early kidney transcriptional and metabolic remodeling at 12 weeks (differentially expressed genes on bulk RNA-seq). High-salt diet induced hypertension (212/157 mmHg by week 17) and 81 differentially expressed kidney genes at week 12 that persisted despite subdepressor imidapril (0 DEGs vs high-salt alone).
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