Molecular biology of components of the renin-angiotensin system during development

Abstract

Evidence for the expression of genes of the renin-angiotensin system (RAS) in the developing kidney is rapidly accumulating. We have recently demonstrated that the fetal kidney expresses the renin gene and that expression of the gene is developmentally regulated. Kidney renin messenger ribonucleic acid (mRNA) levels decrease markedly with maturation, and as maturation unfolds the intrarenal distribution of renin and its mRNA changes from large intrarenal arteries in the fetus to a restricted juxtaglomerular site in the adult animal. These findings demonstrate that renin is synthesized and stored in the aforementioned vascular segments and that expression of the renin gene follows the centrifugal pattern of nephrovascular development. In addition to storing renin, intact kidney microvessels release renin spontaneously and possess a functionally active adenylate cyclase whose stimulation results in a marked increase in renin release. The increase in renin enzymatic activity appears to be due to a recruitment of renin-releasing cells rather than to an increase in the amount of renin secreted per cell. Expression of the angiotensinogen (Ao) gene is also developmentally regulated. Ao mRNA levels are very low in the fetal liver, markedly increasing after parturition, suggesting that some of the complex neurohumoral changes surrounding extrauterine life may regulate the expression of the Ao gene. As in the adult animal, Ao is expressed in fetal kidney, brain and brown adipose tissue. The contribution of these organs to the fetal plasma pool of Ao remains to be determined. However, unlike the adult, the fetal liver may not be the primary source of circulating Ao in the fetus. The distribution of angiotensin-converting enzyme in the developing kidney differs from that of the adult kidney. In human fetuses, the enzyme is located in microvilli and basolateral membranes of proximal tubules, and at the cleft of S-shaped glomeruli and in glomerular capillaries of more mature nephrons. As maturation proceeds, localization in peritubular capillaries becomes manifest and glomerular localization becomes restricted to a few endothelial cells. This changing pattern of enzyme localization may be of importance in the regulation of glomerular and post-glomerular hemodynamics and tubular fluid reabsorption. In summary, the three genes of the RAS are expressed in the fetal kidney. The distribution of the encoding proteins follows a unique developmental pattern that may be important for the early establishment of a paracrine angiotensin(s) generating system.