Salt-Sensitive hypertension (SS-HTN) is associated with an increase in immune cells and pro-inflammatory cytokines, such as IL-6. Additionally, consuming a high salt (HS) diet contributes to the development of SS-HTN, as well as induces renal immune cell activation. We previously showed that intra-renal IL-6 is increased in SS-HTN and can increase blood pressure via reduced sodium excretion. However, no data show a mechanistic link between dietary HS in SS-HTN and inflammation. We hypothesize that HS increases renal osmolarity and IL-6 levels, which precedes the development of SS-HTN. Wt (male) mice were given L-NAME (0.5mg/mL, 2 wks) and then washed-out (1-2wks, Fig 1A ). Mice in early phase (early salt-sensitive, eSS) were then given 1% saline + normal chow (NC) or HS chow (4%) + tap water for 2 days. To develop SS-HTN, mice were given HS for the remainder of the study (SS-HTN, Fig 1A ). Control mice were given NC or HS only. Kidneys were isolated and dissected (cortex + outer medulla) for osmolarity or used for RT-PCR. Serum was used for cytokine analysis (Meso-Scale Discovery). To determine how and where immune cells may be exposed to HS, we assessed the interstitial osmolarity of the renal cortex + outer medulla in both models of eSS. We observed a significant increase in interstitial osmolarity at the eSS stage following 2 days of 1% saline or 4% HS chow, as compared to NC ( Fig 1B ). This increase was not present during SS-HTN. This corresponds with early increases in serum IL-6 levels (1.82±0.3 pg/mL eSS vs. 0.81±0.14pg/mL HS vs . 1.1±0.27pg/mL NC; p<0.05) and renal CD8 + T-cells. We then assessed kidney injury molecule 1 (KIM-1) mRNA levels and saw the greatest increase was also at eSS (4%) (DCt 9.58±0.17 eSS vs. DCt 9.58±0.17, p<0.01). Here, we are the first to show that salt-sensitivity (eSS) promotes increased osmolarity accumulation in the renal interstitium. This also corresponds with the greatest increase in IL-6 and KIM-1, all preceding the development of SS-HTN. These data suggest that HS-induced increases in IL-6 and KIM-1, via increased renal osmolarity, may contribute to the early development of SS-HTN.
Cowley et al. (Mon,) studied this question.