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 01_High_Salt_Diet) or low-sodium diet (LSD 02_Low_Salt_Diet). A subgroup of HSD-fed rats received the ACE (03_High_Salt_Diet+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 early kidney remodeling by week 12, including metabolic and transcriptional alterations suggestive of disrupted tricarboxylic acid cycle activity and impaired oxidative phosphorylation. Intrakidney 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 fibrotic kidney remodeling that is not reversed by subdepressor ACE inhibition.

Electron microscopy

Kidney samples were processed for transmission and scanning transmission electron microscopy (STEM) using standard fixation, embedding, and staining procedures, as described in the Supplementary Methods of the associated publication. Briefly, ultrathin sections were imaged on a Tecnai G2 TEM (Thermo Fisher Scientific, Eindhoven, Netherlands) and correlated with high-resolution STEM overviews (ZEISS FE-SEM Sigma 500, Vienna, Austria). Image analysis was performed by a blinded pathologist using ImageSP Viewer (SYSPROG, Minsk, Belarus) and the built-in measuring tools. For each animal, data from up to four sections averaged.