Differential Changes in End Organ Immune Cells and Inflammation in Salt-Sensitive Hypertension: Effects of Lowering Blood Pressure.

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice.  However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both.  We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN.  SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/mL) in their drinking water for 2 weeks, followed by a 2-week washout period.  Subsequently, the mice received a 3-week 4% high salt diet (SSHTN).  The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks.  In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice.  Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN.  These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.

Differential Changes in End Organ Immune Cells and Inflammation in Salt-Sensitive Hypertension: Effects of Increasing M2 Macrophages.

Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads.  However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN).  Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/mL) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN).  AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet.  Control mice were provided standard diet and tap water.  AVE treatment significantly attenuated BP and inflammation in mice with SSHTN.  Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN.  Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice.  These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses.  Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN.  Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.