Inducible nephron-wide angiotensinogen deletion in mice resulted in a 50% reduction in plasma AGT levels, significantly lower blood pressure, and an attenuated hypertensive response to Ang-II.
Does nephron-wide angiotensinogen deletion reduce blood pressure and attenuate Angiotensin-II-dependent hypertension in mice?
Nephron-derived angiotensinogen may play a role in Angiotensin-II-dependent hypertension, as its deletion in mice lowers blood pressure and attenuates the hypertensive response to Ang-II infusion.
The role of intranephron angiotensinogen (AGT) in blood pressure (BP) regulation is not fully understood. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, whereas proximal tubule-specific deletion of AGT did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP-flanked AGT alleles to achieve nephron-wide AGT disruption after doxycycline induction. Compared to controls, AGT knockout (KO) mice demonstrated markedly reduced renal AGT immunostaining, mRNA, and protein levels; unexpectedly AGT KO mice had reduced AGT mRNA levels in the liver along with 50% reduction in plasma AGT levels. BP was significantly lower in the AGT KO mice compared to controls fed a normal, low, or high Na(+) intake, with the highest BP reduction on a low Na(+) diet. Regardless of Na(+) intake, AGT KO mice had higher plasma renin concentration (PRC) and markedly reduced urinary AGT levels compared to controls. Following angiotensin-II (Ang-II) infusion, AGT KO mice demonstrated an attenuated hypertensive response despite similar suppression of PRC in the two groups. Taken together, these data suggest that nephron-derived AGT may be involved in Ang-II-dependent hypertension, however, a clear role for nephron-derived AGT in physiological BP regulation remains to be determined.
Ramkumar et al. (Fri,) conducted a other in Angiotensin-II dependent hypertension. Inducible nephron-wide AGT deletion vs. Control mice was evaluated on Blood pressure and hypertensive response to Angiotensin-II infusion. Inducible nephron-wide angiotensinogen deletion in mice resulted in a 50% reduction in plasma AGT levels, significantly lower blood pressure, and an attenuated hypertensive response to Ang-II.