Abstract

Accumulating evidence suggests that angiotensin II (ANG II) plays an important role in the complex affair of renal organogenesis. The renin–angiotensin system (RAS) is up‐regulated during renal development and in the perinatal period. On the other hand, inhibition of the RAS, for example by angiotensin‐converting enzyme (ACE) inhibitors, may produce specific renal abnormalities including abnormal renal vessels, failure to develop a renal pelvis and tubular atrophy associated with expansion of the interstitium. AT2 receptors are expressed abundantly during fetal development and are down‐regulated markedly after birth, whereas the abundance of AT1 receptors increases as maturation proceeds. Mice with targeted deletions of genes for angiotensinogen or ACE revealed severe renal abnormalities. In contrast, AT1A, AT1B and AT2 receptor knockout animals exhibited milder abnormalities of the kidney. These findings suggest that AT1 and AT2 receptors are both involved in the development of the nephron, and that ANG II provides signals through both receptors. ANG II exerts in vitro growth‐stimulatory effects on tubular cells. Moreover, ANG II induces synthesis of collagen type IV in tubular cells, a necessary prerequisite for successful basement membrane formation. These effects are mediated through AT1 receptors. Thus, it is feasible that blockade of the RAS during kidney organogenesis leads to a decrease in the growth factor ANG II that may be pivotal for tubular growth and differentiation. On the other hand, ANG II's growth‐stimulatory effects through AT1 receptors may be counterbalanced by AT2 receptor‐mediated apoptosis and growth inhibition. Therefore, alterations in AT2 receptor signalling may alter the delicate balance between growth stimulation and inhibition, leading to alterations in tubular formation.

Correspondence and offprint requests to: Gunter Wolf, MD, Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, University Hospital Eppendorf, Pavilion 61, Martinistr. 52, D‐20246 Hamburg, Germany.

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