Role of angiotensin in the development of the kidney and urinary tract

When perfusion pressure to the kidney falls, e.g., as a result of dehydrati on or mechanical hindrance to the renal arterial blood flow, the release of renin, hence angiotensin (Ang), surges. This feedback regulation is geared to preservation of renal hemodynamic environment by raising systemic blood pressure. We are aware that a surge of renin-angiotensin release also occu rs when there is a mechanical hindrance to urine outflow. This phenomenon o f ureteral pressure-sensitive activation of renin-angiotensin has been here tofore viewed as an error of nature. We have obtained evidence which challe nges this traditional view when we examined strains of mutant mice which ar e completely devoid of either angiotensin type 1 (AT(1)) receptor gene (Agt r1-) or angiotensin type 2 (AT(2)) receptor gene (Agtr2-) as a result of ge netic manipulation of these animals. These strains of mice display varying degrees of urinary tract obstruction. In Agtr2- mice obstructions develop d uring early kidney ontogenesis in ureto, and, in Agtr1- mice, during late o ntogenesis ex utero. One may recall that, throughout its normal ontogenesis, the kidney is twice at risk for obstruction of urine outflow. Thus, in utero the ureter is tra nsiently obliterated. This transient obliteration is believed to protect th e kidney from the high pressure from the cloaca when urine is not yet forme d. During this period, the ureter is surrounded by dense layers of undiffer entiated mesenchymal cells. Subsequent expansive growth that the ureter mus t achieve, therefore, in concert with a timely disappearance of the surroun ding mesenchymal cells. The study in Agtr2- embryos indicated that Ang, thr ough the Agtr2 receptor, promotes disappearance of these mesenchymal cells, and that inactivation of this receptor results in congenital obstructive n ephropathy. Our additional studies in human specimens indeed indicate that many infants with congenital anomalies of the kidney and urinary tract have a significant mutation within the AT(2) gene. Once animals are born, the kidney comes to be of primary importance for pre servation of body fluid homeostasis, and urinary output increases dramatica lly. The large volume of urine predisposes the kidney to obstructive nephro pathy due to the high resistance offered to the urine by the downstream ure ter. Normally, a special device develops within the urinary tract in a time ly fashion, which enables the kidney to collect a bulk of urine, and then t o expel it downward periodically without imposing positive pressure upon th e renal parenchyma. This special device is the renal pelvis. In the studies on Agtr1 null mutant mice, we learned that Ang, through the AT(1) receptor , promotes development of the pelvis shortly after birth, so that inactivat ion of this receptor in Agtr1- mice leads to absence of development of the pelvis, hence to obstructive nephropathy. Collectively, Agtr1 or Agtr2 null mutant mice suffer from urinary tract obs truction. Given that urinary tract obstruction per se is a potent stimulus for Ang generation, Ang is essential for the kidney to escape from obstruct ive injury.