A time-course transcriptomic analysis of hypertension-induced kidney, heart, and liver injury in Dahl salt-sensitive rats

Hypertension is a prevalent condition affecting nearly one in three adults and is a leading cause of cardiovascular diseases and death. Over time, hypertension causes damage to various organs; however, the underlying mechanisms are not completely understood. Therefore, we performed a time-course analysis of different organs (kidney, heart, and liver) in the setting of salt-induced hypertension. The main objective of the study was to understand the dynamic molecular changes in hypertension-driven progressive organ damage. Dahl salt-sensitive (SS) rats (strain: SS/JrHsdMcwi), a well-established model for salt-induced hypertension, were used for the studies. 8-10 weeks old male SS rats were fed a high-salt (HS) diet (4.0% NaCl; Dyets, Inc., D113756) to induce hypertension, along with a control group fed a low salt (LS) diet (purified AIN-76A rodent food containing 0.4% NaCl; D113755). SS rats have a significant (p<0.05) elevation of blood pressure starting from day 7 in 4% HS diet (HS group) as compared to rats fed a LS diet (LS group). Biochemical analysis of urine showed significant (p<0.05) diuresis and albuminuria starting from day 7 in HS group compared to the control group. This was also accompanied and correlated with the significant progressive damage to glomeruli and kidney tubules assessed by histopathology (H&E and Masson’s Trichome staining) and immunostaining of kidney injury marker 1 (Kim-1). A significant increase in kidney weight (1.3-fold; p<0.001, N=10-11 rats/ group) was also observed on week 3 in the HS group as compared to the controls. Further, we found significantly increased heart weight (p<0.05, N=11 rats/group) on week 3 in the HS group, indicating hypertrophy. Separate groups of animals were fed the HS diet without blood pressure measurements to avoid potential confounding factors introduced by telemetry surgery. The rats were sacrificed on days 7, 14, 21, and 35 of the HS diet. Urine, plasma, kidney, heart, and liver samples were collected for the following analyses. Our preliminary transcriptomic analysis revealed dysregulation of multiple genes associated with metabolism, inflammation, and injury in SS rats at different time points of the HS diet. Further, time-course studies are ongoing to understand dynamic transcriptional changes in the kidney, heart, and liver in progressive damage caused by salt-induced hypertension. Thus, the current study provides a comprehensive analysis of biochemical, cellular, and molecular changes with the progression of hypertension-induced damage to the kidney, heart, and liver. Further, it provides a hypertension-driven transcriptional landscape in the kidney, heart, and liver that could be used by other investigators interested in the analysis of salt-induced hypertension. This work is supported by National Institutes of Health Grants R01 DK129227, R01 DK135644, and Department of Veteran Affairs grant I01 BX004024 (to A.S.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.