We have recently reported that NaHCO3- supplementation (drinking water) limits the development of tubular casts and fibrosis in the kidneys of high salt fed Dahl salt-sensitive (SS) rats, independent of lowering systemic arterial pressure. M1 or classically activated macrophages are the first line of defense against infection and release inflammatory cytokines and damage tissue. Conversely, anti-inflammatory macrophages, also called M2 or alternatively activated macrophages, release anti-inflammatory cytokines and promote tissue repair after injury. Much recent evidence implicates macrophage polarization in the progression of numerous disease states including acute kidney injury. However, the role of macrophage polarization in progressive renal injury models such as the Dahl SS rat has not yet been investigated. In the current study we investigated whether NaHCO3- supplementation alters macrophage polarization in Dahl SS rats. 11 week old male Dahl SS rats were either treated with vehicle (0.1M NaCl; n=10) or NaHCO3- (0.1M; n=11) in drinking water for the length of the study. At the beginning of the study, rats were maintained on a 0.4% NaCl diet (low salt, LS: Dyets AIN76A) for 4 days before being switched to an 8% NaCl diet (high-salt, HS) for 14 days. On day 14 of HS, rats were anesthetized with isoflurane (inhalation 2-5%), arterial blood gas measurements taken and both arterial blood (n=5 each group), or the spleen (n=5 each group) and the left kidney excised for flow cytometry analysis. Rats were then humanely euthanized by pneumothorax without recovery from anesthesia.Data were analyzed by ANOVA. Our data indicate that NaHCO3- treatment promoted a robust shift in the renal macrophage phenotype toward M2 macrophages (vehicle M1:0.26±0.03, M2:0.12±0.02 vs bicarbonate M1:0.12±0.02, M2:0.20±0.03 % of total kidney cells respectively, pTREATMENT =0.0002) and that this was associated with reduced tubulointerstitial injury without causing systemic alkalosis in HS fed rats. This shift in macrophage polarization was evident even in Dahl rats treated with NaHCO3- for 3 days while fed LS (vehicle M1:0.30±0.06, M2:0.20±0.05 vs bicarbonate M1:0.16±0.04, M2:0.40±0.02 % of total kidney cells respectively, pTREATMENT =0.007) and occurred prior to the advent of differences in kidney injury in this group. Furthermore, examination of splenic tissue revealed a similar effect of NaHCO3- to promote a predominantly M2 phenotype (vehicle M1:8.6±0.5, M2:6.4±0.5; bicarbonate M1:5.8±0.8, M2:8.3±0.5 % of total splenic cells respectively, pTREATMENT =0.0005). These data indicate that NaHCO3- may be a relatively safe and effective way to modulate macrophage phenotype in vivo and that a shift in macrophage polarization toward regulatory M2 macrophages may underlie some of the protective effects of NaHCO3- treatment on renal function.