Recent advances in the study of renin and angiotensinogen genes: from molecules to the whole body.

The renin-angiotensin system (RAS) plays a key role in the regulation of the circulation and is critically involved in the pathogenesis of several diseases, including hypertension. Renin is synthesized mainly in the kidney and is secreted into the bloodstream. It catalyzes the rate-limiting cleavage of substrate angiotensinogen, which is derived mainly from the liver, to generate angiotensin I. Renin and angiotensinogen genes have been isolated and their structure has been determined by the methods of molecular biology. Renin and angiotensinogen genes are expressed in many tissues, and the tissue-specific regulation of these genes has been studied. The existence of local RASs in contrast to the classical circulating RAS has been suggested, although their exact functional role remains to be determined. Recent molecular analyses have led to a detailed description of the transcriptional mechanism of the renin and angiotensinogen genes, and have made it possible to study the regulation of the expression of these genes in several physiological and pathological states. In addition, several types of transgenic animals have been developed to study the functional importance of the RAS in vivo. Transgenic mice with human renin and human angiotensinogen genes may be a good model of human hypertension. In such mice, the human genes are expressed in the normal tissue-specific pattern, the circulating RAS is activated, and blood pressure is high. Finally, angiotensinogen-deficient mice have also been developed by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver. As a result, they have no plasma immunoreactive angiotensin I and are hypotensive. The profound hypotension in these mice indicates the importance of the RAS in maintaining pressure.