Chronic kidney disease (CKD) is a global disease affecting 10% of the world population (Eckardt et al., 2013). Many patients only start treatment once heavy fibrosis/inflammation are established and drugs available to treat CKD at this stage are limited. It is therefore increasingly necessary to target kidney disease at much earlier stages. Many studies point to impaired vascular function and hypoxia as an early pathophysiological event preceding CKD (Fine & Norman, 2008). Understanding this vascular pathology may help identify new therapeutic targets for early intervention in renal disease. Most models of experimental CKD induce rapid progression to fibrosis, inflammation and renal impairment. Here, we describe a low level, multi-hit approach to induce vascular dysfunction in C57BL6 mice prior to development of renal fibrosis. Mice were anesthetised with isofluorane and implanted with a minipump containing angiotensin II (ANGII; 100ng/kg/min) and a deoxycorticosterone pellet (DOCA; 50mg). On recovery, mice were fed a 3% sodium diet (ANGII DOCA salt mice; n=11) for 4 weeks. Control mice were sham-operated, with implantation of minipumps containing 0.9% saline and a blank pellet and were kept on standard chow (SHAM mice; n=12). In one cohort, blood pressure was measured by tail plethysmography and renal function was measured under Inactin anaesthesia, as previously described (Bailey, Mullins, & Kenyon, 2009). In another cohort (of the same group sizes) mice were killed by cervical dislocation, kidneys were harvested and snap frozen or formalin fixed. The aorta was microdissected and mounted on a wire myograph. By week 4, ANGII DOCA salt mice had elevated systolic blood pressure compared to sham-operated control animals (ANGII DOCA salt: 136.5±3.2mmHg SHAM: 113.3±1.9mmHg, p<0.001). Renal function was unchanged: glomerular filtration rate was similar in both groups (ANGII DOCA salt: 0.15±0.05ml min-1 SHAM: 0.23±0.04ml min-1, p>0.05) and there was no evidence of albuminuria. Collagen staining identified perivascular fibrosis in ANGII DOCA salt mice kidneys. Vascular function also differed in ANGII DOCA salt mice compared to SHAM animals. Aortas from ANGII DOCA salt mice were more responsive to phenylephrine (Mean max response, ANGII DOCA salt: 124.5±14.9 %KPSS SHAM: 90.0±11.8 % KPSS p<0.01) and acetylcholine (Mean max response, ANGII DOCA salt: 5.0±12.4 % relaxation, SHAM: 31.0±7.5 % relaxation) than those from SHAM mice. Our multi-hit model captures a phenotype of hypertension with vascular dysfunction in C57BL6 mice. GFR was normal and the absence of proteinuria is consistent with preserved renal function. We are currently using this model to examine the contribution of purinergic signalling to altered vascular function.