Genetic deficiency of angiotensinogen produces an impaired urine concentrating ability in mice.
Angiotensinogen gene-knockout (Atg-/-) mice lacking angiotensin II exhibit chronic hypotension. The present study was designed to investigate pathophysiology of Atg-/- mice from the renal functional view. Wild-type (Atg+/+) and Atg-/- mice at 10 weeks of age were housed in metabolic cages for 24-hour urine collection. When provided free access to water, Atg-/- mice showed an increased urine output and a decreased urine osmolality compared with Atg+/+ mice. Urinary excretion and plasma levels of vasopressin were significantly higher in mutant mice than in wild-type mice. On the other hand, urinary excretion of aldosterone in mutant mice was suppressed to the levels under the detection limit of the assay system. The mean plasma aldosterone level of Atg-/- mice was suppressed to 30% of that of Atg+/+ mice. Plasma levels of creatinine, endogenous creatinine clearance, and urinary electrolyte excretion were not different between these mice. In Atg+/+ mice, urine osmolality was markedly increased from 1929 +/- 21 to 3314 +/- 402 mOsm/kg during water deprivation, whereas this parameter in Atg-/- mice did not change significantly (from 1413 +/- 121 to 1590 +/- 92 mOsm/kg). Urinary vasopressin excretion increased during water deprivation from 0.24 +/- 0.04 and 0.70 +/- 0.08 to 0.42 +/- 0.06 and 2.31 +/- 0.35 ng/mg creatinine in wild-type and mutant mice, respectively. Histologic study revealed interstitial inflammation, and atrophic changes in the tubules and papilla in Atg-/- mice. In conclusion, a genetic deficiency of angiotensinogen produced an impaired urine concentrating ability and tubulointerstitial lesions, indicating the critical role of angiotensinogen in developing normal tubular function and construction.
Kihara
M
M
Department of Internal Medicine II, Yokohama City University School of Medicine, Japan.
Umemura
S
S
Sumida
Y
Y
Yokoyama
N
N
Yabana
M
M
Nyui
N
N
Tamura
K
K
Murakami
K
K
Fukamizu
A
A
Ishii
M
M
D000450:Aldosterone / Q000097:blood / Q000652:urine; D000804:Angiotensin II / Q000172:deficiency; D000808:Angiotensinogen / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D003404:Creatinine / Q000097:blood / Q000652:urine; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007671:Kidney Concentrating Ability / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine; D014667:Vasopressins / Q000097:blood / Q000652:urine; D014868:Water Deprivation / Q000502:physiology
D014667:Vasopressins; D000808:Angiotensinogen; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium; D003404:Creatinine; D011188:Potassium