Introduction: The responses to chronic angiotensin (Ang) II infusions of gene-targeted mice lacking kidney angiotensin-converting enzyme (ACE), in terms of intrarenal Ang II accumulation, hypertension, sodium and water retention are all blunted or absent. The objective of this study was to determine if these reduced responses were associated with changes in the intrarenal renin-angiotensin system (RAS). METHODS: Mice lacking intrarenal ACE (ACE10/10) were generated by targeted homologous recombination placing the expression of ACE only in macrophages. As a result, these mice have normal circulating ACE levels, but no kidney ACE. Wild-type (WT) mice of the same background (C57Bl/J) served as controls. Mice were subjected to sham-operation or subcutaneous infusion of Ang II for two weeks (n=6-10, 400 ng/kg/min via osmotic minipump). Mean arterial pressure (MAP) was followed by telemetry. At the end of the experiment, the kidneys were collected for analysis. Ang II content was measured by RIA. Renal abundance of ACE, angiotensinogen (AGT) and Ang II receptor type 1 (AT1R) were determined by Western Blot in total kidney homogenates. Results: At baseline, the MAP of WT and ACE 10/10 mice was similar 110 ± 4 mmHg vs. 109 ± 3 mmHg respectively (p>0.05). However, when subjected to chronic Ang II infusions, the hypertensive response was blunted in ACE 10/10 mice (129 ± 6 mmHg) vs. WT (146 ± 5 mmHg; P<0.05). Also, intrarenal Ang II accumulation was lower in ACE10/10 mice (724 ± 81 fmol/g) vs. WT (1130 ± 105 fmol/g, p<0.05). In non-treated mice, intrarenal RAS components analysis revealed that the absence of ACE in ACE10/10 mice was accompanied by a significant reduction in AGT (0.41 ± 0.06) and increased AT1R expression (1.32 ± 0.05) when compared to WT (normalized to 1.00, p<0.05 in both instances). Importantly, after chronic Ang II infusions, AGT, ACE and AT1R expression increased in WT (1.36, 1.26 and 1.17 fold increase respectively compared to non-treated WT, p<0.05) but not in the ACE10/10 mice (1.19, 1.06, 0.89 fold increase respectively compared to non-treated ACE10/10, p>0.05). Conclusion: The blunted hypertension and Ang II accumulation of mice devoid of kidney ACE in response to Ang II infusions is associated with a failed induction of renal AGT and the AT1R.

Genistein and exercise are independently purported to abate cardiovascular disease, thus, in this study we aimed to examine the effects of a 6 week treatment with genistein (300 mg/kg day, G) or placebo control (0G) with (EX) or without exercise (SED) in ovariectomized (OVX) and intact (INT) Sprague‐Dawley rats randomly divided into the following groups; OVX‐EX, OVX‐G/EX, OVX‐SED, OVX‐G/SED, INT‐EX, INT‐G/EX, INT‐SED, INT‐G/SED. Final rat weight, heart weight, and tibia length were all significantly decreased in OVX‐G/EX (n=7) compared to OVX‐EX (n=6). Heart weight and tibia length were significantly increased in OVX‐EX (n=6) compared to OVX‐SED (n=6). Femur weight was significantly increased in INT‐EX (n=6) and INT‐G/EX (n=9) compared to INT‐G/SED (n=5). Tibia length was significantly increased in INT‐EX (n=6) compared to INT‐G/SED (n=5). There were no changes in total liver weight, left liver lobe weight, total liver weight/body weight ratio, femur length, tibia weight, fat pad weight, uterine weight between groups. At the end of the study; systolic BP and mean arterial pressure (MAP) were increased in OVX‐G/EX, MAP was decreased in INT‐G/SED (n=5), pulse pressure was increased in OVX‐EX (n=6) and decreased in INT‐EX (n=6) and cardiac work was decreased in INT‐EX (n=6). Interestingly, there was an EX‐induced increase in aorta luminal diameter of INT‐EX (762.5±9.6 μm, n=4) compared to INT‐SED (723.1±7.5 μm, n=5), without change in aortic wall thickness. Our results show that a 6 week treatment of genistein and/or EX can contribute towards changes in both physical characteristic and blood pressures, and that INT and OVX rats do not respond similarly. Supported by NIH (1R15DK071625‐01A2), MWU intramural & CHS funds.

No abstract