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NF-κB is an evolutionarily conserved eukaryotic transcription factor that plays a role in many important developmental and immune-related processes by activating target gene expression. The goal of these experiments was to define the sequences required for a sea anemone NF-κB's intrinsic transactivation activity by using mutant proteins with serial deletions of the N- and C-terminal sequences. Deletion mutants were constructed that were missing the C-terminal 15, 32 or 47 amino acids (aa) or the N-terminal 17, 27 or 47 aa of the 440 aa NF-κB protein from the starlet sea anemone, Nematostella vectensis (Nv), a simple model organism in the phylum Cnidaria. These Nv-NF-κB mutants were expressed as GAL4 fusion proteins in yeast, and their transactivation activities were assessed by LacZ reporter gene assays. The deletion of 47 aa from either the N terminus or the C terminus of NF-κB completely inactivates the transactivation function of Nv-NF-κB. In addition, we identified proline-258 in the center ...

Primary aldosteronism (PA) is present in up to 20% of patients with treatment-resistant hypertension (TRH). Investigation for PA in patients with TRH is recommended by current guidelines after medication nonadherence is excluded. Studies using therapeutic drug monitoring (TDM) have shown that >50% of patients with TRH are nonadherent to their prescribed antihypertensive medications. However, the relationship between the prevalence of PA and medication adherence as confirmed by TDM has not been previously assessed. A retrospective analysis from a hypertension referral clinic showed that prevalence of PA in adherent patients with TRH by TDM was significantly higher than in nonadherent patients (28% vs 8%, P

Growth and regeneration of one tissue within an organ compels accommodative changes in the surrounding tissues. However, the molecular nature and operating logic governing these concurrent changes remain poorly defined. The dermal adipose layer expands concomitantly with hair follicle downgrowth, providing a paradigm for studying coordinated changes of surrounding lineages with a regenerating tissue. Here, we discover that hair follicle transit-amplifying cells (HF-TACs) play an essential role in orchestrating dermal adipogenesis through secreting Sonic Hedgehog (SHH). Depletion of Shh from HF-TACs abrogates both dermal adipogenesis and hair follicle growth. Using cell type-specific deletion of Smo, a gene required in SHH-receiving cells, we found that SHH does not act on hair follicles, adipocytes, endothelial cells, and hematopoietic cells for adipogenesis. Instead, SHH acts directly on adipocyte precursors, promoting their proliferation and their expression of a key adipogenic gene, peroxisome proliferator-activated receptor γ (Pparg), to induce dermal adipogenesis. Our study therefore uncovers a critical role for TACs in orchestrating the generation of both their own progeny and a neighboring lineage to achieve concomitant tissue production across lineages.

Skeletal patterning in the sea urchin embryo requires coordinated signaling between the pattern-dictating ectoderm and the skeletogenic primary mesenchyme cells (PMCs); recent studies have begun to uncover the molecular basis for this process. Using an unbiased RNA-Seq-based screen, we have previously identified the TGF-s superfamily ligand, LvBMP5-8, as a skeletal patterning gene in Lytechinus variegatus embryos. This result is surprising, since both BMP5-8 and BMP2/4 ligands have been implicated in sea urchin dorsal-ventral (DV) and left-right (LR) axis specification. Here, we demonstrate that zygotic LvBMP5-8 is required for normal skeletal patterning on the left side, as well as for normal PMC positioning during gastrulation. Zygotic LvBMP5-8 is required for expression of the left-side marker soxE, suggesting that LvBMP5-8 is required for left-side specification. Interestingly, we also find that LvBMP5-8 knockdown suppresses serotonergic neurogenesis on the left side. While LvBMP5-8 overexpression is sufficient to dorsalize embryos, we find that zygotic LvBMP5-8 is not required for normal DV specification or development. In addition, ectopic LvBMP5-8 does not dorsalize LvBMP2/4 morphant embryos, indicating that, in the absence of BMP2/4, BMP5-8 is insufficient to specify dorsal. Taken together, our data demonstrate that zygotic LvBMP5-8 signaling is essential for left-side specification, and for normal left-side skeletal and neural patterning, but not for DV specification. Thus, while both BMP2/4 and BMP5-8 regulate LR axis specification, BMP2/4 but not zygotic BMP5-8 regulates DV axis specification in sea urchin embryos.

The sea urchin larval skeleton offers a simple model for developmental pattern formation. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA-seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter which promotes a ventral accumulation of sulfated proteoglycans that is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for the sea urchin skeletal patterning.

Nonadherence to drug therapy poses a significant problem in the treatment of patients with presumed resistant hypertension. It has been shown that therapeutic drug monitoring (TDM) is a useful tool for detecting nonadherence and identifying barriers to treatment adherence, leading to effective blood pressure (BP) control. However, the cost-effectiveness of TDM in the management of resistant hypertension has not been investigated.A Markov model was used to evaluate life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in resistant hypertension patients receiving either TDM optimized therapy or standard best medical therapy. The model ran from the age of 30 to 100 years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Cost analyses were performed from a payer's perspective. Deterministic and probabilistic sensitivity analyses were conducted.In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of €3854 and €3922, respectively. Given a willingness-to-pay threshold of €35,000 per QALY gained, the probability of TDM being cost-effective was 95% or more in all age groups from 30 to 90 years. Results were influenced mostly by the frequency of TDM testing, the rate of nonresponders to TDM, and the magnitude of effect of TDM on BP.Therapeutic drug monitoring presents a potential cost-effective healthcare intervention in patients diagnosed with resistant hypertension. Importantly, this finding is valid for a wide range of patients, independent of sex and age.

Background: Non-adherence to anti-hypertensive medications poses a significant problem in the treatment of patients with presumed resistant hypertension (RH). Our recent study has shown that therapeutic drug monitoring (TDM) is a useful tool not only for detecting medication non-adherence but also exploring the barrier to antihypertensive drug therapy, resulting effective BP control. However, the cost effectiveness of TDM in the management of resistant hypertension has not been investigated. Method: A Markov model was used to evaluate life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in RH patients receiving either TDM optimized therapy or standard best medical therapy (BMT). The model ran from the age of 30 to 100 years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Results: In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of є3,854 and є3,922, respectively. Given a willingness-to-pay threshold of є35,000 per QALY gained, the probability of TDM being cost-effective compared to BMT was ≥95% in all age groups from 30 to 90 years. Incremental cost-effectiveness ratios were influenced mostly by the annual frequency of TDM testing, the rate of non-responders to TDM, and the magnitude of effect of TDM on systolic blood pressure (Figure). Conclusion: Therapeutic drug monitoring presents a potential cost-effective health care intervention in patients diagnosed with RH. Importantly, this finding is valid for a wide range of patients, independent of gender and age.

The objective of this study was to compare the antihypertensive efficacy and safety of losartan and mibefradil. 324 outpatients (57 +/- 9.2 years) with mild to moderate hypertension were randomly allocated in a double-blind fashion to receive 50 mg of losartan or mibefradil once daily p.o. for 6 weeks after 2 weeks of placebo run-in. Titration was then forced to 100 mg of losartan or mibefradil for an additional 6 weeks. Patients were assessed at baseline, 6 and 12 weeks. The primary efficacy variable was change in predose sitting diastolic (SDBP) and systolic (SSBP) blood pressure at 12 weeks. Secondary variables included change in mean 24-hour ambulatory blood pressure and comparison of safety and tolerability. Both treatments lowered SSBP and SDBP at 6 and 12 weeks (week 6: mibefradil -14/-9 mm Hg; losartan -12/-7 mm Hg) (P

Cardiac remodeling after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of the present study was to assess the effects of chronic treatment with a novel angiotensin AT(1) receptor antagonist 2-butyl-4-(methylthio-)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl ](1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), on cardiac remodeling and left ventricular dysfunction in a rat model of large myocardial infarction. Rats were subjected to permanent ligation of the left coronary artery and were treated for six weeks with placebo or HR720 (3 mg/kg/day) initiated 24 h after surgery. Sham-operated rats served as normal controls. Mean arterial blood pressure, the maximum rate of rise of the left ventricular systolic pressure (dP/dt(max)), left ventricular end-diastolic pressure, left ventricular inner diameter and circumference, septal thickness, left ventricular collagen content and heart weight were measured at the end of the treatment. HR720 treatment versus placebo attenuated the cardiac hypertrophy (heart weight/body weight: 2.88+/-0.08 mg/g vs. 3.16+/-0.09 mg/g, P0.05), reduced interstitial collagen content (3. 47+/-0.28% vs. 5.25+/-0.45%, P0.01), limited infarct size (33.0+/-3. 0% vs. 41.5+/-2.3%, P0.05), decreased left ventricular end-diastolic pressure (13.7+/-2.2 vs. 21.4+/-1.6 mm Hg, P0.01) and improved dP/dt(max) (9000+/-430 vs. 6000+/-840 mm Hg/s, P0.05). The present results demonstrate that chronic treatment with the angiotensin AT(1) receptor antagonist HR720 can limit infarct size, partially prevent cardiac hypertrophic remodeling and improve left ventricular function in rats with myocardial infarction.

Besides playing a role in blood-pressure regulation and salt and fluid homeostasis, the octapeptide angiotensin II mediates cell growth and differentiation. Its effects are dependent on angiotensin receptors, of which both AT1 and AT2 receptors are extensively described. In cardiac hypertrophy and heart failure, angiotensin receptors are differentially regulated. It is established that AT1 receptors induce cell growth, while AT2 receptors have been associated with growth inhibition, differentiation, and apoptosis. The availability of receptors controlling cell function within a broad spectrum for a single hormone and the regulation of these receptors during cardiac hypertrophy and failure emphasize a complex role for angiotensin II in cardiac pathogenesis. Due to their functional properties, AT1 and AT2 receptors might counteract each other in cell growth processes. Therefore, the current clinical use of specific AT1 receptor antagonists raises questions as to the role of the AT2 receptor in disease processes such as cardiac hypertrophy and failure. Under AT1 receptor antagonist treatment, AT2 receptors are overexposed to angiotensin II. This article describes a possible role of angiotensin II through its angiotensin receptors AT1 and AT2 in cardiac hypertrophy and heart failure.

Physiological and pharmacological implications of AT1versus AT2receptors. Angiotensin II (Ang II) has diverse physiological actions that lead, for instance, to increases in extracellular volume and peripheral vascular resistance and blood pressure, and it has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis, and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone, and the release of arginine vasopressin. In each condition, the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum arginine vasopressin levels, or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor exerts antiproliferative actions and promotes neurite outgrowth, an effect accompanied by significant changes in the expression pattern of growth/differentiation-related genes.

Angiotensin II mediates its effects through angiotensin receptors. The use of specific angiotensin receptor ligands and the cloning of these receptors allows their classification. So far, the AT1, AT2 and atypical angiotensin II receptors are recognised. The AT1 receptor is responsible for the classical effects of the renin-angiotensin system such as vasoconstriction, renal salt and water retention, central osmo-control and stimulation of cell growth. The function of the AT2 receptor is far from clear but this receptor appears to be important in fetal development, cell growth inhibition and differentiation processes. This review describes the angiotensin receptors and focuses on the possible functions of the AT2 receptor.

Objective: Blockade of angiotensin AT1 receptors has been shown to prevent cardiac remodeling and improve left ventricular function and survival after myocardial infarction (MI). However, the timing of initiation of treatment has not been fully elucidated. Therefore, the purpose of the present study was to compare the effects of very early (30 min after MI), early (3 and 24 h after MI) and delayed (7 days after MI) treatments with the angiotensin AT1 receptor antagonist fonsartan (HR 720) on cardiac morphological and hemodynamic parameters in a rat model of MI-induced heart failure and to establish the therapeutic window for the start of treatment. Methods: Male Wistar rats underwent coronary ligation and were randomized fonsartan (HR720) treatment starting 30 min, 3 h, 24 h and 7 days after MI or no treatment. Treatment was continued up to 6 weeks post MI. Results: Fonsartan (HR720) treatment attenuated cardiac hypertrophy when treatment started 30 min or later after MI, limited infarct size when treatment initiated 3 and 24 h after MI, decreased left ventricular end-diastolic pressure when treatment started 3 h to 7 days after MI, and improved d P /d t max when treatment commenced 24 h and 7 days after MI compared to untreated infarct group. Conclusion: Our results show that angiotensin AT1 receptor blockade with fonsartan (HR720) produced the best cardioprotective effects when treatment was started 3 to 24 h after MI although a start of treatment 7 days following MI still could improve functional parameters. These results suggest an optimal time window for the start of treatment with angiotensin AT1 receptor antagonists seems to be between 3 and 24 h post MI.

Objective: We investigated the effect of chronic treatment with the new Na+/H+-exchange inhibitor, cariporide, on cardiac function and remodelling 6 weeks after myocardial infarction (MI) in rats. Methods: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats. Results: Compared to sham animals, untreated MI-controls developed pronounced heart failure after 6 weeks. Basal left ventricular end-diastolic pressure (in mmHg) was reduced in the groups in which cariporide was started 1 week pre (16.0±1.7) or 30 min (12.5±1.1), 3 h (11.8±1.0) and 24 h (13.0±2.5) after MI compared to untreated MI-controls (22.4±1.5; P

The renin-angiotensin system (RAS) is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is production of the active peptide angiotensin II (Ang II). Because Ang II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the RAS. Angiotensin II may also be involved in end-organ damage in hypertension, heart failure, and vascular disease. At least two subtypes of angiotensin II receptors have been identified: AT1 and AT2. The AT1 mediates all of the known actions of Ang II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, and increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known regarding the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects. Angiotensin II AT1 receptor antagonists (AT1RA) inhibit the RAS at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of Ang II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1RA may provide end-organ protection by blocking Ang II effects via the AT1 receptor, yet leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction (MI) and other conditions resulting from structural alterations in the heart, kidney, and vasculature.

Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone and the release of arginine vasopressin (AVP). In each condition the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum AVP levels or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor reportedly exerts antiproliferative effects and promotes neurite outgrowth, an effect accompanied by significant changes in the gene expression pattern of growth- and differentiation-related genes.

Die Charakterisierung der ANG-II-Rezeptorsubtypen hat uns mit neuen Werkzeugen ausgestattet, mit denen wir unser Wissen um die verschiedenen Funktionen von ANG II erweitern konnten. Mit der Entwicklung der nicht-peptidergen AT1-Antagonisten, der Sartane, konnte ein neues therapeutisches Prinzip zur Behandlung der Hypertonie in die klinische Praxis eingefuhrt werden. Die Sartane blockieren den AT1-Rezeptor und bieten dabei hohe therapeutische Sicherheit verbunden mit niedriger Toxizitat. Weiterhin konnte fur die AT1-Rezeptorantagonisten gezeigt werden, das sie, ahnlich den ACE-Hemmem, Herz- und Gefasmorphologie und -funktion verbessern konnen. Die Mechanismen, die diesen zusatzlichen Wirkungen der AT1-Blocker zugrunde liegen, werden noch nicht vollstandig verstanden. Da alle AT1-Antagonisten basierend auf den initial beschriebenen Imidazolderivaten entwickelt wurden und alle uber eine hoch selektive Blockade des AT1-Rezeptors wirken, konnte man erwarten, das sie sich auch klinisch ahnlich verhalten. Dennoch kann man bezuglich ihrer pharmakologischen Eigenschaften und bei einigen der neueren Antagonisten auch bezuglich der chemischen Struktur Unterschiede finden. Inwieweit sich diese Unterschiede tatsachlich auf die klinische Praxis auswirken, wird aber erst mit dem wachsenden Einsatz der AT1-Antagonisten und weiterfuhrenden Studien endgultig zu beantworten sein.

The effects of moxonidine on blood pressure, heart rate and sympathetic tone were studied in conscious spontaneously hypertensive rats. Intravenous moxonidine (80 nmol) transiently increased blood pressure without affecting heart rate or splanchnic nerve activity. Moxonidine (20-80 nmol) given into the fourth cerebral ventricle dose-dependently lowered mean arterial pressure, heart rate and sympathetic outflow (maximally by 60 +/- 3 mm Hg, 148 +/- 10 beats min(-1) and 15 +/- 3 microV). Moxonidine was more effective by this route than after the injection into the lateral ventricle. Clonidine (20-80 nmol) produced an initial pressor response after both intracerebroventricular routes of administration. A decrease in blood pressure was observed only when clonidine was given into the fourth ventricle. Clonidine decreased heart rate and splanchnic nerve activity similarly like moxonidine when the substances were given into the fourth ventricle. The data imply that the hypotensive effect of moxonidine is related to central sympathoinhibition. The main site of this action appears to be in the brainstem region.

Objective : Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2+-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the “therapeutic window” for the start of therapy. Methods : MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (d P /d t max) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5–1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). Results: Six weeks after MI, MAP was lowered, LVEDP increased and d P /d t max reduced. Mibefradil treatment increased basal MAP in groups 3–5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3–6 and, after MEX, in all groups. d P /d t max was increased in groups 3–4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3–6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3–4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3–5. Conclusion: Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.

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.