Functional role of collecting duct renin angiotensin system

• Applicant: Professor Dr. Frank Schweda
• Subject Area: Anatomy and Physiology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 248902650

The renin angiotensin system (RAS) is centrally involved in the regulation of the salt and water balance of the body as well as in blood pressure regulation. Moreover, the RAS plays a major role in the pathophysiology of cardiovascular and renal diseases. The activity of the RAS cascade is controlled by the enzymatic activity of the protease renin. Renin is mainly synthesized and stored in the so called juxtaglomerular cells (JG cells) that are located in the vessel walls of the renal afferent arterioles and released from these cells into the circulation. Besides this classical circulating RAS the existence of local renin angiotensin systems in various tissues has been demonstrated in recent years. Even in the kidney renin is produced not only in JG cells but also in tubular cells. Especially renin expression in renal collecting ducts has been matter of interest since it is markedly upregulated in renin dependent forms of arterial hypertension as well as in diabetes mellitus and therefore might be involved in the pathogenesis or the pathophysiological consequences of these diseases. Moreover, the renin promoter is highly active in the collecting duct during nephrogenesis. Together with the fact that pharmacological blockade of the RAS during pregnancy or mutations in genes encoding the RAS components, result in disorders of tubular development, these data suggest that the local tubular RAS might be involved in kidney nephrogenesis. Although expression and regulation of renin in collecting ducts and intrarenal generation of angiotensin II has been demonstrated in several studies, the functional role of this local tubular RAS is largely unknown. This lack of knowledge mainly results from the fact that classical experimental interventions, such as pharmacological blockade or genetic deletion of single RAS components, affect both the local and the circulating RAS. Accordingly these approaches do not allow discriminating between local and systemic renin angiotensin systems. To circumvent this problem, we have generated a mouse line with collecting duct specific deletion of the renin gene. In the current project we will use this mouse line to investigate the role of collecting duct renin for the control of blood pressure under physiological and pathophysiological (renal hypertension, diabetes mellitus) conditions.

• DFG Programme: Research Grants