Unopposed stimulation of the angiotensin AT2 receptor in the kidney.

candesartan, telmisartan and others, and AT2-recepEffects of angiotensin II in the kidney tor ligands/antagonists as for example PD123177, PD123319 and CGP42112, was the basis for the identiAngiotensin II (ANG II ), the major effector molecule fication and characterization of ANG II receptor of the renin–angiotensin system (RAS), exerts numersubtypes. Currently, two main angiotensin-receptor ous actions on kidney function and structure. Under subtypes, AT1 and AT2, have been cloned and pharmaphysiological conditions, ANG II modulates glomercologically characterized, which display a heterogenular filtration by constricting efferent and afferent eous distribution in peripheral tissues and in the brain arteriolar blood vessels and glomerular mesangial cells [overview: 2,5,6 ]. The existence of further subtypes to modify filtration coefficient, mechanisms which enable the kidney to autoregulate glomerular filtration such as the AT3and AT4 receptor, is still controverrate in a broad range, when systemic blood pressure sial. In the human kidney, only a single gene encoding and/or renal perfusion pressure change [1]. ANG II for the AT1 receptor is expressed, which is localized also facilitates renal sodium retention through several on chromosome 3. In rodents, however, AT1a and mechanisms: via a decrease in medullary blood flow AT1b receptor isoforms exist, which are localized on and renal interstitial pressure, both leading to a chromosome 17 and 2, respectively, and bear over 90% decrease in sodium excretion, via enhanced sodium identity. In humans, the gene for the AT2 receptor is reabsorption through an enhanced filtration fraction localized on the X-chromosome. Both, the AT1 and leading to augmentated peritubular capillary colloidthe AT2 receptor belong to the seven-transmembraneosmotic pressure [1], or via direct effects in the proxdomain superfamily of receptors, but the amino acid imal tubule as for example stimulation of the Na+/H+ sequence of the AT1 receptor is only 34% identical exchanger [overview: 2]. ANG II-induced aldosterone with the AT2 receptor sequence [overview: 6 ]. secretion from the adrenal gland also contributes to The distribution of the AT1 receptor isoforms within renal sodium retention [1]. Furthermore, ANG II has the kidney has not yet been extensively studied. In also been implicated in cellular growth and differrats, the AT1a receptor, expressed predominantly in entiation in the kidney, for example in angiogenesis vascular smooth muscle, is most abundant in the occurring during glomerular differentiation [3] and glomerular mesangial area, the vascular component of nephrosclerosis [4]. The role of ANG II as a growth the juxtaglomerular apparatus and the terminal portion factor has been demonstrated in a number of studies of the afferent arteriole [7–9]. In contrast, AT1b using fibroblasts, adrenal cortical-, vascular smooth mRNA levels seem to be much lower in the kidney, muscle-, or cardiac cells, and growth modulating effects and relatively high concentrations are only found of ANG II have also been shown in mesangial and within the lining of the papilla and the proximal tubular cells of the kidney [overview: 5]. portion of the ureter. Recent findings have demonstrated that in the rat kidney, AT1a mRNA is upregulated by dietary sodium whilst AT1b mRNA is Angiotensin II receptor subtypes in the kidney downregulated, indicating that these receptors are not only differentially regulated but might also mediate In an endeavour to block the RAS more specifically different renal functions. Compared to AT2 receptors, and, thereby, avoid unwarranted side effects of ACE AT1 receptors dominate by far the adult human [10] inhibitors, novel non-peptidergic ANG II receptor and rat [7] kidney, while AT2 receptors only represent antagonists have been developed. The development of 5–10% of the ANG II receptors, predominantly located highly specific and selective AT1-receptor antagonists in the renal capsule, larger vessels and to a lower such as losartan, valsartan, eprosartan, irbesartan, extent in the glomerular area [7–9]. However, in the prenatal rat kidney, AT2-receptors account for more Correspondence and offprint requests to: Dr O. Chung, Institute of than 80% of total ANG II receptors [2,11] suggesting Pharmacology, Christian-Albrechts-University Kiel, Hospitalstrasse 4, D-24105 Kiel, Germany. an important role during renal development.