Genetic deficiency of angiotensinogen produces an impaired urine concentrating ability in mice

Abstract

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.

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

“…An increased water turnover occurs in AgtϪ/Ϫ mice because they have a partial nephrogenic diabetes insipidus resulting from a developmental impairment of renal concentrating mechanisms caused by a perinatal lack of angiotensin peptides (21,47). The elevated daily water intake in AgtϪ/Ϫ mice is probably secondary to fluid loss from the kidney, which would have a dehydrating effect.…”

“…As well, they appeared to ingest appropriate volumes of water in response to periods of water deprivation. As a consequence of a developmental disorder of their renal concentrating mechanisms (21), AgtϪ/Ϫ mice lose greater volumes of urine than do WT C57BL6 mice. Accordingly, we observed that AgtϪ/Ϫ mice deprived of water for 7 h, incurred approximately the same loss of body weight as did WT mice deprived of water for 24 h. When water was returned to the mice, AgtϪ/Ϫ mice drank amounts of water during the next hour that were still more than the intakes of the WT mice that had been deprived of water for 24 h.…”

“…These mice exhibit lower arterial blood pressure, higher plasma renin levels, lower body weight, and an increased fluid turnover compared with wild-type (WT) mice (1,21,22,26,47,48). The lower body weight results from reduced white adipose tissue mass (26).…”

“…The lower body weight results from reduced white adipose tissue mass (26). The increased fluid turnover is due to a renal urinary concentrating defect resulting from a lack of angiotensin during kidney development (21,47). In the case of mice with a homozygous lack of the Agt gene (AgtϪ/Ϫ mice), most do not survive the first postnatal week unless they are rescued by fluid and electrolyte replacement during the postnatal period or angiotensin treatment (47).…”

What Have We Learned from Gene Targeting Studies for the Renin Angiotensin System of the Kidney?

“…Ang II contributes to these features of mammalian kidneys through its constrictive action on renal arteries (20)(21)(22) and its regulatory effect on iron transports (23)(24)(25). Recently, Okubo et al (26) and Kihara et al (27) reported that Agt-I-mice have severely impaired ability for urinary concentration during experimental ECF volume depletion. The lack of urine concentrating capacity is attributed to an impaired responsiveness of the kidney to vasopressin (AVP) rather than to an impaired secretory process of AVP, because administration of a maximal dose of AVPfailed to substantially increase the urine osmolality of Agt-l-micz.…”