Angiotensin II is an important effector molecule controlling blood pressure and volume in the cardiovascular system. Its importance is manifested by the efficacy of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Angiotensin II interacts with two pharmacologically distinct subtypes of cell-surface receptors, AT1 and AT2. AT1 receptors seem to mediate the major cardiovascular effects of angiotensin II. Here we report the isolation by expression cloning of a complementary DNA encoding a unique protein with the pharmacological specificity of a vascular AT1 receptor. Hydropathic modelling of the deduced protein suggests that it shares the seven-transmembrane-region motif with the G protein-coupled receptor superfamily. Knowledge of the AT1 receptor primary sequence should now permit structural analysis, definition of the angiotensin II receptor gene family and delineation of the contribution of AT receptors to the genetic component of hypertension.

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The peptide angiotensin II is the effector molecule of the reninangiotensin system. All the haemodynamic effects of angiotensin II, including vasoconstriction and adrenal aldosterone release, are mediated through a single class of cell-surface receptors known as AT1 (refs 1, 2). These receptors contain the structural features of the G-protein-coupled receptor superfamily. We show here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that this phosphorylation is associated with increased activity of Jak2. The Jak family substrates STAT1 and STAT2 (for signal transducers and activators of transcription) are rapidly tyrosine-phosphorylated in response to angiotensin II. We also find that Jak2 co-precipitates with the AT1 receptor, indicating that G-protein-coupled receptors may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors.

ACE-related carboxypeptidase (ACE2) may counterbalance the angiotensin (ANG) II-promoting effects of ACE in tissues where both enzymes are found. Alterations in renal ACE and ACE2 expression have been described in experimental models of diabetes, but ACE2 activity was not assessed in previous studies. We developed a microplatebased fluorometric method for the concurrent determination of ACE and ACE2 activity in tissue samples. Enzymatic activity (relative fluorescence unit [RFU] ⅐ g protein ؊1 ⅐ h ؊1 ) was examined in ACE and ACE2 knockout mice and in two rodent models of diabetes, the db/db and streptozotocin ( and r ‫؍‬ ؊0.522, respectively). We conclude that in renal cortex from diabetic mice, ACE2 expression is increased at the posttranscriptional level. The availability of an assay for concurrent measurement of ACE and ACE2 activity should be helpful in the evaluation of kidney-specific alterations in the balance of these two carboxypeptidases, which are involved in the control of local ANG II formation and degradation. Diabetes 55

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Clinicopathologic review of 134 patients originally diagnosed as having nodular (pseudosarcomatous) fasciitis is presented. In 114 patients with 116 lesions, no recurrence of the lesion was noted. Of the 114 patients, 85% were younger than 50 years of age, and the forearm and arm were the most common sites of presentation. Nonrecurrent lesions rarely exceed 4 cm and 71% were smaller than 2 cm. In at least six instances, incompletely resected lesions never recurred. Though all lesions were histologically reminiscent of reparative mesenchymal tissue, four subtypes--the reactive type, the densely cellular type, those with osteoid or cartilaginous metaplasia, and the so-called proliferative fasciitis--were distinguished from the majority of lesions that conform to the description given by Kornwaler. Recurrence of the tumor was noted in 18 patients. Fifteen of 18 lesions recurred within two years, and two more recurred at 30 months following initial excision. In all these cases, review of the histology and clinical course led to a revision of the original diagnosis. The greatest number of errors was made in incorrectly classifying of inflammatory fibrous histiocytoma. Recurrence of a lesion originally diagnosed as nodular fasciitis should lead to a careful reappraisal of the pathologic findings.

Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension. IntroductionHypertension affects more than 1.5 billion people worldwide and is a key contributor to stroke and cardiovascular and kidney disease. The importance of the renin-angiotensin system (RAS) in the origins of this disorder is underscored by the blood pressure-lowering effects of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers. However, plasma renin activity, the clinical index used to determine systemic RAS status, is distributed over a wide range in hypertensive subjects (1, 2). This observation prompts the suggestion that alterations in tissue-specific RAS, not detected by plasma renin activity, may underlie hypertension. The kidneys play a central role in long-term blood pressure control through their regulation of sodium and fluid balance. Because renal salt retention is strongly influenced by Ang II and there is a complete RAS along the nephron, it has been suggested that increased local Ang II formation may induce hypertension. Indeed, using gene-targeted mice, we and others have shown that increased intrarenal Ang II formation results in hypertension (3-6). As a whole, these observations suggest that renal Ang II synthesis has important consequences for nephron function and the development of hypertension. However, precisely how the intrarenal generation of Ang II elevates blood pressure is not known. Therefore, we tested the hypothesis that, in conditions in which the intrarenal RAS becomes activated, local Ang II synthesis enhances sodium and water reabsorption along the nephron. In addition, we postulated that inhibiting intrarenal Ang II formation effectively protects against hypertension.