Tissue-specific Renin-angiotensin System Research Articles

Angiotensin Converting Enzyme Inhibitors: Interaction Issues in Patients with Glaucoma and Arterial Hypertension. Review

The purpose of the review is to evaluate the interaction of angiotensin-converting enzyme inhibitors in patients with glaucoma and concomitant arterial hypertension using literature data. Glaucoma is the main cause of blindness and visual impairment, as well as the main cause of irreversible blindness worldwide. Pharmacotherapy, laser or surgical treatments are used to reduce IOP levels, as well as prevent deterioration of visual field defects. However, 40 % of patients develop glaucomatous neuropathy despite ongoing therapy. This prompts the investigation of alternative causes of damage to the optic nerve, and abnormal blood pressure levels, both too low and too high, are considered as a possible risk factor. Arterial hypertension occurs in 48–65 % of patients with glaucoma and is the most common systemic disease in patients with glaucoma. Currently, angiotensin converting enzyme (ACE) inhibitors are considered the “gold standard” in the treatment of arterial hypertension, in the pathogenesis of which activation of the renin-angiotensin system (RAS) plays an important role. The renin-angiotensin system (RAS) is a hormonal system responsible for regulating blood pressure and fluid and electrolyte balance in the body. Local tissue-specific RAS were found, including in the structures of the eyeball: cornea, aqueous humor, iris, ciliary body, vitreous body, retina. These data indicate that the local RAS plays an important role in the regulation of the physiology of the eye and may become a target in the development of new antiglaucoma drugs. Animal studies, as well as studies in various patient groups, show that systemic antihypertensive drugs that inhibit the RAS, such as ACE inhibitors, reduce IOP. These studies support the concept that RAS inhibitory drugs may be potential antiglaucoma drugs in the future, as ACE inhibitors can improve the outflow of intraocular fluid, thereby reducing IOP.

Myocardial Angiotensin Metabolism in End-Stage Heart Failure

BackgroundThe myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy. ObjectivesThis study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy. MethodsFifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients. ResultsAngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity. ConclusionsThe failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

Circadian rhythm of blood pressure and the renin-angiotensin system in the kidney.

Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

OS 32-02 EFFECTS OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON VAGINA AND CARDIAC EXPRESSION OF RAAS COMPONENTS IN FEMALE SPONTANEOUSLY HYPERTENSIVE RATS

Abstract The role of the renin angiotensin aldosterone system (RAAS) and the gene variants of its components in hypertension have been investigated in various studies. A local tissue-specific renin-angiotensin system (local RAS) has considered as a regulator of cardiovascular physiology and homeostasis. However, no report has described the vagina protective efficacy of RAS inhibitors including ARB and ACEI. Therefore, we aim to investigate the effect of ARBs and ACEI on the vagina and cardiac expression of the local renin-angiotensin components. 16 week-old female spontaneously hypertensive rats (SHRs) were randomly divided into control, hypertension, benazepril-treated (10 mg/kg.d), valsartan-treated (15 mg/kg.d), and ben + val (5 mg/kg.d + 7.5 mg/kg.d)-treated groups. Real-time polymerase chain reaction was used to detect mRNA expression of angiotensin II type 1 receptor (AT1R), ACE, ACE2, and angiotensin-(1-7) receptor (MasR). The cardiac structure and function were measured by echocardiography. BP was higher in SHR than in WKY rats at baseline, after 12 weeks treatment, BP of SHR markedly reduced in every administered group. The antihypertensive effects were similar for the two treatment groups. Expression levels of AT1R and ACE in vagina and cardiac were significantly elevated in the hypertension group compared to the control group. The mRNA expression of antihypertensive components such as ACE2 and MasR were greater increased in the benazepril-treated group compared to valsartan group. Benazepril and valsartan, decreased the mRNA expression of ACE and AT1R, but increased the mRNA expression of ACE2 and MasR in cardiac and vagina tissue. RAS inhibitors such as ARBs and ACEI play a protective role in heart and vessels. These results indicate that the change tendency of RAS components expression in vagina were consistent with heart after administrated. It is likely that vagina is also one of the target organs that could be protected by the anti-hypertensive drugs. However, the precise potential mechanism remains unclear.

Abstract 602: Mass Spectrometry Based Characterization of Angiotensin Metabolism in ACE2 Deficient Mice Treated with RAS Blockers

The Renin-Angiotensin-System is a peptide hormone cascade being responsible for the regulation of blood pressure and fluid balance through a sophisticated signaling network. During recent years the local Renin-Angiotensin-System (RAS) moved increasingly into the focus of research as the expression of multiple angiotensin processing enzymes had been reported for tissues. Nevertheless, scientific progress in this field is hampered due to the obvious presence of technical caveats in the analysis of the local RAS, which are indicated by a tremendous variation of tissue angiotensin levels reported in the literature. Hence, in order to assess the functions of the local RAS in different tissues, a solid and reproducible assay for the measurement of endogenous angiotensin peptide levels in tissues would be essential. We developed a novel mass-spectrometry-based method allowing the quantification of up to 10 angiotensin metabolites in tissue samples simultaneously. This novel tool was tested for applicability in murine studies by measuring tissue and plasma levels of angiotensin metabolites in wildtype and ACE2 knockout mice treated with various RAS-interfering drugs. The study provided deep insights into the systemic and tissue specific RAS revealing drug specific responses. As expected, the knockout of ACE2 resulted in increased Angiotensin II levels in hearts of knockout animals while the kidneys were only moderately affected. Enalapril treatment significantly lowered Angiotensin II levels in all investigated tissues. Surprising tissue specific effects were observed regarding other angiotensin metabolites, which underlines the importance of the comprehensive analysis of the RAS for conclusive interpretation of pharmacologic studies and allows to draw conclusions about expression levels of RAS-enzymes in the tissue of interest. Mass spectrometry based multiplex quantification of tissue angiotensin peptides (Tissue RAS-Fingerprinting) is a potent analytic tool for applications in basic science and drug development. Multiplex analysis of the tissue RAS provides new insights that might lead to the development of novel drugs and therapeutic concepts for the treatment of cardiovascular diseases in the future.

Activating types 1 and 2 angiotensin II receptors modulate the hypertrophic differentiation of chondrocytes

A local tissue-specific renin–angiotensin system (local RAS) has been identified in many organs. However, no report has described the role of a local RAS in the hypertrophic differentiation of chondrocytes. To examine the role of a local RAS in the hypertrophic differentiation, we activated angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) separately in the cell line ATDC5, which involves differentiation from mesenchymal stem cells to hypertrophic chondrocytes. Activation of AT1R suppressed and activation of AT2R enhanced the expression of markers of hypertrophic differentiation, including type X collagen, matrix metalloproteinase 13 and runt-related transcription factor 2.

Aging and the Renin-Angiotensin System

Angiotensin II (Ang II), the dominant effector molecule of the renin-angiotensin system (RAS), exerts its effects on binding of 2 pharmacologically distinct rhodopsin-like G protein–associated receptors, the type 1 and the type 2 (AT1 and AT2) receptors.1 Human cells express a single AT1 receptor, whereas 2 isoforms, AT1A and AT1B with 95% of amino acid sequence identity and similar affinities for Ang II, are present in rodents. The AT1A receptor, the closest murine homologue to the human AT1 receptor, predominates in most tissues, including heart, kidney, and brain. Expression of the AT2 receptor is ubiquitous in fetal tissues of rodents and humans and it decreases after birth, remaining at a low level in adulthood in adrenal medulla, uterus, ovary, vascular endothelium, and distinct brain areas.2 Arterial blood pressure is regulated by diverse pathways that include vasomotion, regulation of sodium and water excretion by the kidney, and activity of the central and sympathetic nervous systems. Circulating Ang II through activation of the AT1 receptor contributes to an increase in blood pressure and promotes renal tubular sodium and water retention.3,4 The discovery of tissue-specific RAS components in the heart, kidney, brain, and immune system led to the definition of local RAS that exerts organ-specific functions and can operate independently or in close interaction with circulating RAS components. A role of intrarenal RAS in hypertension has been suggested by cross-transplantation experiments showing that the development of hypertension is predominantly dependent on the presence of the AT1A receptor in the kidney.5 Based on the evidence that activation of the brain RAS regulates fluid balance and energy metabolism, the involvement of altered brain RAS signaling in high- and low-renin forms of hypertension has been proposed.6 Intriguing actions of …

Presence and Physiologic Function of the Renin–Angiotensin System in Mouse Lacrimal Gland

To investigate the expression, localization, and physiologic function of renin-angiotensin system (RAS) components in the mouse lacrimal gland. Lacrimal glands and cultured lacrimal gland fibroblasts from wild-type (WT) BALB/c (H-2(d)) mice were used. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to determine the expression and localization of the RAS components, prorenin/renin, angiotensin-converting enzyme (ACE), angiotensin II, angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R) in the normal mouse lacrimal gland. To examine the change in tear secretion, mice received ARB (AT1R blocker) or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Prorenin/renin and ACE were identified in myoepithelial cells around ducts and acini and in blood vessels. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland.

Involvement of the Skeletal Renin-Angiotensin System in Age-Related Osteoporosis of Ageing Mice

The local tissue-specific renin-angiotensin system (RAS) was identified. The aim of this study was to investigate the role of local bone RAS in the osteoporosis of aging mice. Twelve-month-old and two-month-old male mice were respectively assigned to the ageing and young groups. The tibias and femurs were collected for an analysis of histomorphology, bone mass, and gene and protein expression. H&E staining and micro-CT measurement showed a loss of the trabecular bone network and decrease of bone mineral density in the proximal tibial metaphysis of the aged mice. The PCR results indicated the significant up-regulation of renin and angiotensinogen (AGT) mRNA expression in both the tibia and femur of the ageing mice. Western blotting data showed that the tibial angiotensin II protein expression was significantly increased in the ageing group. The enhancement of renin and AGT expression in the bone tissue resulted in the increased production of angiotensin II which plays an important role in the pathology of age-related osteoporosis.

Inhibition of angiotensin‐converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin‐angiotensin system

The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, 'local' tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling.

Specific receptor for angiotensinogen on human renal cells

Background We recently demonstrated the existence of an angiotensinogen (AGT) receptor on placental cells. It has been established that there is a tissue-specific renin–angiotensin system (RAS) in the human kidney. This study focused on whether human renal proximal tubule epithelial cells possessed an AGT receptor. Methods Human renal proximal tubule epithelial cells were cultured in plastic wells. Binding assays were carried out by adding iodinated angiotensinogen ( 125I-AGT) to each culture well, with or without unlabeled AGT. The cells were washed, lysed, and the radioactivity was measured. Results Human renal proximal tubule epithelial cells bound 125I-AGT in a time-dependent manner. This binding was competitively and specifically inhibited by unlabeled AGT. Bound 125I-AGT was competitively displaced by AGT. Acid washing removed 30% at 8 h, indicating that 70% bound AGT had been internalized. Scatchard plot binding analysis showed that the identified AGT receptor possessed a single class of high-affinity binding sites ( K d = 1.73 nmol, B max = 23.39 pmol/10 6 cells). Conclusion The results of this study provide evidence for the presence of an AGT receptor on human renal proximal tubule epithelial cells. Our finding suggests that the AGT receptor may be an integral component of the renal RAS.

Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule.

The purpose of this study was to evaluate the physiological significance of a tissue renin-angiotensin system in the proximal tubule of the kidney. To accomplish this, we produced mice that express human renin (hREN) under the control of the kidney androgen-regulated promoter (KAP), which is androgen responsive. One of the lines expressed the hREN transgene primarily in the kidney. Renal expression of the transgene was undetectable in females but could be induced by testosterone treatment. Because the renin-angiotensin system is species specific, we bred KAP2-hREN mice with the mice expressing human angiotensinogen under the same promoter (KAP-hAGT) to produce offspring that expressed both transgenes. We measured mean arterial blood pressure (MAP) in the carotid artery of double-transgenic and control mice using radiotelemetry. Double-transgenic female mice had a normal baseline MAP (116 +/- 4 mmHg, n = 8), which increased by 15 mmHg after 2 wk of testosterone treatment, and returned to baseline after elimination of the testosterone pellet. The change in arterial pressure paralleled the change in plasma testosterone. There was no MAP change in testosterone-treated control littermates. We conclude that dual production of renin and angiotensinogen in the renal proximal tubule can result in a systemic increase in arterial pressure. These data support a role for a tissue-specific renin-angiotensin system in the renal proximal tubule that contributes to the regulation of systemic blood pressure.

Role of angiotensin II in the progression of diabetic nephropathy-therapeutic implications.

During the last four decades, the renin–angiotensin system (RAS) has emerged as an important endocrine factor in the chain of physiological blood pressure regulation and water–electrolyte balance, and as a substantial determinant of cardiovascular and renal remodelling. For >20 years it has been established that angiotensinogen is produced in the liver, and is in turn cleaved by the proteolytic enzyme reninreleasing angiotensin I, which is converted to angiotensin II by the converting enzyme (ACE) in the lung and other organs. It is well known that this circulating RAS is suppressed in patients with diabetic nephropathy [1]. A turning point in the research on the RAS was the finding of local tissue-specific RAS in several organs. Such local systems were found not only in glomerular and tubulointerstitial cells of the kidneys but in almost all organs of the human body. Micropuncture studies of the nephron revealed 1000 times higher concentrations of angiotensin II in proximal tubular and interstitial fluid than in systemic blood [2]. What is the role of this local renal RAS systems? Under physiological conditions, the glomerular RAS is a main player in the regulation of glomerular filtration by influencing the resistance predominantly of the vasa efferentia and to a less degree of the vasa afferentia, and by altering the effective filtration surface. The tubulointerstitial RAS is presumed to stimulate sodium and bicarbonate reabsorption in proximal tubules (by activation of the luminal Naþ/Hþ exchanger, basolateral Na/HCO3 – cotransporter and Naþ/Kþ ATPase). Both systems seem to play an important role in the compensatory mechanisms induced by nephron injury. Excessive local angiotensin II concentration increases glomerular permeability by a variety of mechanisms such as a high intraglomerular transmembrane pressure, suppressed synthesis of negatively charged proteoglycans and nephrin, and enhanced synthesis of extracellular matrix components [3]. In proximal renal tubules, exposed to a protein load, increased angiotensin II synthesis induces interstitial fibrosis. There are two main angiotensin II receptors (AT1 and AT2). Both have been cloned and well characterized [3]. Most biological effects of angiotensin II (Figure 1) are mediated by the AT1 receptor via intracellular activation of phospholipase, inhibition of adenylate cyclase and stimulation of tyrosine phosphorylation [4]. The physiological function of the AT2 receptor is not so well elucidated; however, it is generally presumed that its activation antagonizes the effects transduced by AT1 receptor stimulation (Figure 1). Moreover, the existence of a third type of angiotensin family receptor was recognized (AT4). Stimulation of that receptor by angiotensin IV results in increased plasminogen acivator inhibitor-1 (PAI-1) synthesis in proximal tubular and endothelial cells in the kidney [5,6]. The existence of other types of receptors is still postulated.

Detection of a receptor for angiotensinogen on placental cells

BackgroundCurrent evidence indicates that there may be a tissue-specific renin-angiotensin system (RAS) in the human placenta. To better define the placental RAS, this study sought to determine whether placental derived cells possessed a receptor for angiotensinogen (AGT), a rate limiting component of the RAS. MethodsA human placenta–derived cell line, CRL-7548, a highly purified AGT and iodine-125–labeled angiotensinogen (125I-AGT) were used in this study. The cells were seeded in 35-mm diameter plastic wells, cultured for 2 days in fetal bovine serum–Dulbecco’s modified Eagle’s medium to reach about 80% to 90% confluence, 2 × 104 cells/well and passed in Dulbecco’s modified Eagle’s medium free of fetal bovine serum before experimentation. A quantity of 3 μg of 125I-AGT was added to each well at zero time. ResultsThe cells rapidly bound 125I-AGT in a time dependent manner with saturation being achieved in 2 to 4 h. This binding was competitively inhibited by unlabeled AGT. Prior addition of a 100-fold excess of unlabeled AGT resulted in a 54% decrease in maximal binding. Bound AGT was also competitively displaced by AGT. Addition of a 200-fold excess of unlabeled AGT displaced 70% of the bound 125I-AGT. Thus, approximately 30% of the total binding can be attributed to nonspecific binding. An acid wash (0.2 mol/L acetic acid, 0.5 mol/L NaCl, pH 2.5) at 4°C removed 46% of the bound 125I-AGT. An acid wash is known to dissociate cell surface ligand-receptor complexes, but does not remove internalized ligand. ConclusionThe results of this study provide evidence for the existence of an AGT receptor on placenta-derived cells. This is the first report of an AGT receptor.

A method to evaluate the renin-angiotensin system in rat renal cortex using a microdialysis technique combined with HPLC-fluorescence detection.

A microdialysis (MD) technique, combined with HPLC-fluorescence (FL) detection, was developed for the evaluation of the tissue-specific renin-angiotensin system (RAS) in the rat renal cortex. An MD probe constructed with a hydrophilic hollow fiber dialysis tubing, AN69, showed high recovery (more than 50%) in vitro for all four angiotensins: angiotensin I (Ang I), Ang II, Ang III, and Ang (1-7). Angiotensins, successfully derivatized with m-BS-ABD-F, a water-soluble fluorogenic reagent that has a 2,1,3-benzoxadiazole (benzofurazan) structure, could be simultaneously determined by coupled-column HPLC. The detection limit for Ang I, Ang II, Ang III, and Ang (1-7) were 94, 44, 47, and 83 fmol, respectively. All these peptides were determined with good linearity (0.0125-3.1 microM, equivalent to 0.25-62 pmol, correlation coefficient >0.99) and good precision (recovery >91%). In the MD studies, generation of Ang (1-7) and Ang II was observed when Ang I was perfused, and Ang (1-7) was the major biologically active angiotensin found in the dialysate samples. The concentration of Ang (1-7) and Ang II in the dialysate samples showed good correlation to that of Ang I in a MD perfusate (20-100 microM). Cleavage of Ang I to Ang (1-7) was drastically suppressed by the co-perfusion of phoshoramidon (0.5-5 mM), an inhibitor of neprilysin, which generates Ang (1-7) from Ang I. These results are consistent with the previously reported characteristics of tissue-specific renal RAS, suggesting that our MD/HPLC-FL system may have the potential to be employed to evaluate tissue-specific RAS in the rat renal cortex.

Genetic manipulation of the renin-angiotensin system: targeted expression of the renin-angiotensin system in the kidney

The renin-angiotensin system is a classic endocrine system that also exists within individual tissues. All components of the renin-angiotensin system (RAS) are expressed in the kidney suggesting the potential for local production and action of angiotensin II. Although the importance of the kidney in hypertension is unequivocal, our understanding of the functional significance of intrarenal production of angiotensin II remains incomplete. Using genetic manipulation of the mouse genome we generated a novel transgenic model expressing human angiotensinogen specifically in the proximal tubule cells of the kidney. Herein I describe the generation and physiologic characterization of this model, and discuss the implications of our findings in terms of the genetics of human hypertension. The experimental results presented support the hypothesis that a tissue-specific RAS cascade exists in the kidney of this transgenic model, and that this system may play an important role in blood pressure (BP) and renal homeostasis in this model.

A unifying hypothesis for the renin–angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway

JAK-STAT pathway is a recently encountered intracellular signal transduction system. The pathway is utilized by numerous cytokines, growth factors, and hormones for gene expression and a variety of biological activities. Hematopoiesis is regulated by many cytokines and growth factors that support the proliferation and differentiation of progenitor cells in the bone marrow. JAK-STAT pathway arises as the most common signalling cascade of a wide range of cytokines and/or growth factors in propagation of physiological and pathological/neoplastic hematopoiesis. On the other side, renin–angiotensin system (RAS) includes not only the classic circulating endocrine system controlling blood pressure and electrolyte homeostasis, but also tissue-specific RASs with autocrine and/or paracrine functions. Preliminary data suggest the involvement of the RAS components in normal and pathologic hematopoiesis, although the precise mechanism of action has not been elucidated yet. We have hypothesized, in this report, that JAK-STAT pathway serves as a point of crosstalk between the components of the locally present RAS in the bone marrow and hematopoiesis. Demonstration of a local RAS in the bone marrow with clarification of the postreceptor signalling events may play a consequential role not only for further clarification of normal hematopoiesis but also novel therapeutic approaches in pathologic/neoplastic conditions.

Regional distribution of the angiotensinogens in human placentae

Angiotensinogen is the substrate for the enzyme renin. In addition to the well-characterized low molecular weight forms of angiotensinogen, a high molecular weight form (HMrA) comprises about 15 per cent of the total angiotensinogen in plasma of pregnant women. In the current study the different forms of angiotensinogen were quantitated in different regions of the placenta. The highest concentration of total angiotensinogen was found in the chorion laeve followed by the amnion. It was found that HMrA was the major form of angiotensinogen in all regions of the placenta, accounting for 72, 67, 63, and 59 per cent of the total angiotensinogen in the chorion laeve, chorion plate, amnion, and chorion frondosum, respectively. There was a significant correlation between the distribution of total renin and HMrA. This data in conjugation with previous data indicate that HMrA should be considered a significant component of the renin angiotensin system in the human pregnant state. It is suggested that HMrA may be a component of a tissue specific renin angiotensin system that occurs in the placenta.