Females sex is protective in the development of proteinuria and renal macrophage infiltration in Dahl salt-sensitive rats

Hypertension poses significant risks to cardiovascular and kidney health, with salt-sensitive hypertension being a major contributor to chronic kidney disease (CKD). In Dahl salt-sensitive (SS) rats, hypertension develops in two phases: an initial primary phase during the first week of a high-salt diet. Phenotypes observed in this period are thought to be involved in the initiation of hypertension. The secondary phase occurs during the second two weeks of high salt and is characterized by reduced filtration capacity and kidney damage. Elevated proteinuria, a key biomarker of this transition, is strongly linked to CKD progression. This study explores the sex differences in the early phase of hypertension in SS rats, focusing on proteinuria and renal inflammation. We hypothesize that females will be protected from proteinuria during the primary phase, which will be associated with reduced renal inflammation and injury compared to male SS rats. To test this hypothesis, we conducted experiments using male and female SS rats fed either a control salt (CS, 0.4% NaCl) or a high-salt (HS, 4.0% NaCl) diet for 7 days. Urine was collected every 24 hours to assess proteinuria and kidney injury markers. At the end of the study, kidneys were collected for histological analysis. In male SS rats, urinary protein was significantly higher than CS-fed rats by day 2 of the HS diet (CS: 18±2 vs. HS: 61±6 mg/day, p=0.0071) and remained so throughout the 7 days of HS. In contrast, proteinuria was not higher in female SS rats fed HS compared to those fed CS (p=0.21 comparing groups). Preliminary analysis of urinary CCL2, a chemokine involved in recruiting monocytes, revealed a significant increase in males after day 1 of HS (CS: 336±22 vs. HS: 773±101 pg/day, p=0.0003). No significant difference was observed in females (p=0.14 comparing groups). Similarly, kidney staining for iba1, a macrophage activation marker, found increased macrophage infiltration in male rats after 7 days of HS compared to those maintained on CS (p=0.022). There were no significant differences between CS and HS females (p=0.94). Regression analysis found a significant correlation between urinary protein and iba1 staining in all rats (p=0.0002), suggesting proteinuria may contribute to macrophage infiltration. In conclusion, female SS rats are protected from proteinuria during the initial phase of hypertension, which is associated with reduced urinary CCL2 and macrophage infiltration into the kidney. Ongoing studies are using RNAseq analysis to identify transcriptomic changes that may contribute to the observed sex differences. Studies funded by R01HL152166 to LE 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.