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13BN26 rats was nearly 30?mmHg lower than that of the SS rats. Together, these results indicate that it is the greater expression of p67phox��not p22phox, gp91phox, p47phox, or Rac 1��that is associated with greater levels of renal medullary NAD(P)H oxidase activity on the HS diet and greater salt sensitivity in SS rats compared to SS. 13BN26. To determine the functional relevance of p67phox in the development OPHN1 of salt-sensitive hypertension in SS rats, we generated a p67phox?/? model in the genomic background of SS rats using zinc-finger nucleases (ZFNs) ( Geurts et?al., 2009?and?Geurts et?al., 2010) (for details, see the Experimental Procedures). Genomic DNA of p67phox-null mutant (p67phox?/?) rats was sequenced. Sequencing results suggested there was a 5?bp deletion (GAGAA) in the genomic sequence of p67phox?/? rats ( Figure?3A). The p67phox?/? rats were also validated by western blot experiments ( Figure?S3). In order to further demonstrate that there CCI-779 concentration was no functional p67phox in p67phox?/? rats, respiratory burst experiments were performed. p67phox is known to be critically involved in the respiratory burst of macrophages ( Maehara et?al., 2009?and?Noack et?al., 1999). We obtained macrophages from the peritoneal space of 6- to 7-week-old p67phox?/? rats and wild-type (WT) littermates fed the HS diet for 14?days ( De Miguel et?al., 2010). The respiratory burst response to phorbol 12-myristate 13-acetate (PMA) stimulus in the p67phox?/? rats was completely abolished compared to the WT littermates ( Figure?3B). We concluded that we had successfully generated the p67phox?/? rats. p67phox?/? rats and their WT littermates were used for the BVD523 following phenotypic studies. We first examined the effect of disrupting p67phox on blood pressure. Baseline MAP was not different between the WT and p67phox?/? rats at 6?weeks of age when fed the LS diet ( Figure?4A). MAP between WT and p67phox?/? rats was statistically different on days 10 and 14 of the HS diet (p?
