Nephrotoxicity of angiotensin inhibition during the perinatal period.
As the only ex utero mechanism for the removal of nitrogenous waste, the mammalian kidney achieves some 50-fold increase in urine production during the perinatal period when the placental circulation becomes no longer available as a functional dialyzer. This urine is efficiently removed from the kidney by the renal pelvis, a smooth muscle structure unique to mammals, which develops during the perinatal period. We found that mutant mice completely devoid of angiotensinogen or its type 1 receptor, as well as wild-type neonates given an ACE inhibitor, fail to develop a renal pelvis or a ureteral peristaltic movement. These structural and functional defects in the urinary tract are followed by severe obstructive injury of the renal parenchyma. The ability of angiotensin to directly induce the pelvis is demonstrated in an organ culture system, in which treatment with angiotensin induces the characteristic smooth muscle layer in the wild type, but not in homozygous null mutants. Upregulation of both renal angiotensin content and type 1 receptor at the renal hilum are also demonstrated in the wild type during the transition from intra- to extra-uterine life. By inducing the timely development of the renal pelvis, angiotensin thus facilitates the removal from the renal parenchyma of the urine that promptly increases at birth, thereby effectively preventing a buildup of intrarenal pressure and a consequent development of dysmorphic kidney.
Miyazaki
Y
Y
Department of Pediatrics, Vanderbilt University Medical Center Nashville, Tenn., USA.
Ichikawa
I
I
D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen / Q000172:deficiency; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000209:etiology*; D007682:Kidney Pelvis / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency; D014551:Urinary Tract / Q000254:growth & development
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000808:Angiotensinogen