title: Possible role for nephron-derived angiotensinogen in angiotensin-II dependent hypertension.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah nirupama.ramkumar@hsc.utah.edu.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Ramkumar
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Matias
authors.initials: M
authors.lastname: Calquin
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Shuping
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Medical Science, Tokai University, Isehara, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.affiliation: Institute of Medical Science, Tokai University, Isehara, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000808:Angiotensinogen / Q000172:deficiency*; D000818:Animals; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009399:Nephrons / Q000502:physiology*; D012982:Sodium, Dietary / Q000009:adverse effects*
chemical_list: D012982:Sodium, Dietary; D000808:Angiotensinogen; D000804:Angiotensin II
keywords: Angiotensinogen; blood pressure; kidney; liver