GENETIC DEFICIENCY OF ANGIOTENSINOGEN PRODUCES AN IMPAIRED URINE CONCENTRATING ABILITY IN MICE

Angiotensinogen gene-knockout (Atg(-/-)) mice lacking angiotensin II e xhibit chronic hypotension. The present study was designed to investig ate pathophysiology of Atg(-/-) mice from the renal functional view. W ild-type (Atg(+/+)) and Atg(-/-) mice at 10 weeks of age were housed i n metabolic cages for 24-hour urine collection. When provided free acc ess to water, Atg(-/-) mice showed an increased urine output and a dec reased 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 a ldosterone in mutant mice was suppressed to the levels under the detec tion limit of the assay system. The mean plasma aldosterone level of A tg(-/-) mice was suppressed to 30% of that of Atg(+/+) mice. Plasma le vels of creatinine, endogenous creatinine clearance, and urinary elect rolyte excretion were not different between these mice. In Atg(+/+) mi ce. urine osmolality was markedly increased from 2929 +/- 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 dep rivation from 0.24 +/- 0.04 and 0.70 +/- 0.08 to 0.42 +/- 0.06 and 2.3 1 +/- 0.35 ng/mg creatinine in wild-type and mutant mice, respectively . Histologic study revealed interstitial inflammation, and atrophic ch anges in the tubules and papilla in Ag-/- mice. In conclusion, a genet ic deficiency of angiotensinogen produced an impaired urine concentrat ing ability and tubulointerstitial lesions: indicating the critical ro le of angiotensinogen in developing normal tubular function and constr uction.