The role of angiotensin II in the feedback control of renin gene expression

 This study aimed to characterize the influence of endogenous angiotensin II on renal renin gene expression during different states of a stimulated and of a suppressed renin system. To this end the renin system in male Sprague Dawley rats was stimulated by unilateral renal artery clipping (0.2 mm clip), by furosemide (60 mg/kg per diem) or isoproterenol (160 μg/kg per diem), and by ingestion of a low-salt diet (0.02%), or was suppressed by setting a contralateral renal artery clip (0.2-mm clip) or by ingestion of a high-salt diet (4%). During the last 2 days of these different treatment regimens, the animals were treated with the angiotensin II AT1 receptor antagonist losartan (40 mg/kg per diem) and renal renin mRNA levels were assayed. Renin gene expression was stimulated four- to fivefold by renal artery clipping and isoproterenol infusion, two- to threefold by furosemide and a low-salt diet, and about fourfold by losartan. Additional treatment with losartan potentiated the stimulatory effects of a low-salt diet, of furosemide and of isoproterenol infusion on renin gene expression, whilst there was no significant additional effect of losartan on renin gene expression in clipped kidneys. Both contralateral renal artery clipping and a high-salt diet decreased renin mRNA levels to about 50% of the control value. In rats with a unilateral clip, additional losartan treatment caused renin mRNA to increase to about 350% of the control value in the contralateral kidney but to only 110% of the control value in animals on a high-salt diet. These findings suggest that the enhanced formation of angiotensin II during a low-salt intake, during tubular inhibition of salt reabsorption or during β-adrenoreceptor activation plays a relevant negative feedback role in the activation of the renin gene. Moreover, in rats with one hypoperfused kidney, angiotensin II could be involved in the inhibition of renin gene expression in the contralateral kidney. In hypoperfused kidneys, however, and in animals on a high-salt diet, angiotensin II appears to play only a minor feedback role in the regulation of the renin gene. Received: 10 September 1996 / Received after revision: 17 February 1997 / Accepted: 25 February 1997     

Role of the macula densa in the control of renal renin gene expression in two-kidney/one-clip rats

This study was designed to examine whether macula densa function is involved in the changes of renal renin gene expression upon acute hypoperfusion of one kidney. To block macula densa function, rats with free access to salt and water were subcutaneously infused with furosemide (12 mg/day) for 6 days. Then, 4 days after the start of the infusion, the left renal arteries were clipped with 0.2-mm silver clips and renin mRNA levels in ipsilateral and contralateral kidneys, as well as plasma renin activities (PRA), were determined 48 h after clipping. In non-clipped animals furosemide increased PRA from 10 to 47 ng angiotensin I · h^–1 · ml^–1 and raised renin mRNA levels in both kidneys 2.5-fold. In vehicle-infused animals, clipping of the left renal artery increased PRA to 37 ng angiotensin I · h^–1 · ml^–1 and led to a 5-fold rise of renin mRNA levels in the ipsilateral kidneys and to a suppression to 20% of the control values in the contralateral kidneys. PRA values in clipped and furosemide-infused animals were 45 ng angiotensin I · h^–1 · ml^–1. In these animals renin mRNA levels increased in the ipsilateral kidneys to similar absolute values as in vehicle-infused rats, whilst contralateral renin mRNA levels fell to about 25% of the respective controls. These findings indicate that the stimulations of renin gene expression by inhibition of macula densa salt transport and by renal artery clipping are not additive, suggesting that the macula densa mechanism may participate in the stimulation of renin gene expression upon hypoperfusion. The macula densa mechanism, however, appears to be not essentially involved in the suppression of renin gene expression in the contralaterals to stenosed kidneys.     

Evaluation of the brain and kidney renin-angiotensin system and oxidative stress in neonatal handled rats

The aim of this study was to test the hypothesis that the renin‐angiotensin system (RAS) components, as well as the oxidative stress system, would respond to early environmental changes. Thus, we have evaluated the effects of neonatal handling on both brain and kidney RAS and oxidative stress. Pups were divided into two groups: nonhandled and handled. The procedure consisted of handling them for 1 min/day in the first 10 days of life. On days 1, 5, and 10, animals were killed by decapitation. Blood samples were collected and the brain and kidneys were removed. Renin, AT₁, and AT₂ mRNA expression were evaluated through RT‐PCR. Angiotensin II (ANG II) serum concentration was also measured. An increased ANG II concentration, brain and kidney AT₂ mRNA expression were demonstrated. The kidney mRNA AT₁ expression was decreased. There was also a kidney lipid peroxidation increase and a brain superoxide dismutase and catalase decrease. In conclusion, handling in the neonatal period induces the activation of the angiotensinergic system, as well as modulates its mRNA receptor expression. The oxidative stress balance system seems not to be involved. © 2011 Wiley Periodicals,Inc. Dev Psychobiol 54: 706–713, 2012.     

Prostaglandins are involved in the stimulation of renin gene expression in 2 kidney-1 clip rats

This study was done to obtain information about a possible involvement of prostaglandins in the renal baroreceptor mechanism regulating renin secretion and renin gene expression. To this end the effect of the cyclooxygenase inhibition was examined on renin secretion and on renal renin gene expression in 2 kidney-1 clip rats. The influences of the cyclooxygenase inhibitors indomethacin (2mg/kg twice a day) and meclofenamate (8 mg/kg twice a day) on renal renin m-RNA levels, on plasma renin activity (PRA) and on blood pressure were measured 2 days after clipping the left renal arteries of male Sprague-Dawley rats with 0.2 mm clips. In sham-clipped animals, indomethacin and meclofenamate had no significant effect on basal PRA and renin m-RNA levels. In vehicle-treated animals unilateral renal artery clipping increased blood pressure from 120±4.1 to 150±6.1 mmHg, increased PR6A from 7.4±1.6 to 27.6±3.8 as expressed in nanograms of angiotensin I per hour per millilitre, increased renin m-RNA levels of clipped kidneys from 105±5.9% of standard to 482.6±56% of standard and decreased renin m-RNA levels of contralateral kidneys from 116±9.7% of standard to 34±9.0% of standard. While blood pressure, PRA and renin m-RNA levels of the contralateral kidneys were virtually unchanged by the cyclooxygenase inhibitors indomethacin and meclofenamate, renin gene expression in the clipped kidney was markedly influenced by inhibition of prostaglandin synthesis. Both cyclooxygenase inhibitors attenuated the increase of renin m-RNA levels in response to clipped to 280±26% of standard and 261±35% of standard after application of indomethacin or meclofenamate. These findings suggest that intact prostaglandin formation is at least partially required for the stimulatory effect of low renal perfusion pressure on renin gene expression.     

Positive feedback regulation of angiotensin II-AT1B receptor gene expression in rat adrenal glands

 This study aimed to investigate the role of endogenous angiotensin II (ANGII) in the upregulation of ANG-II AT₁ receptors in adrenal glands during a low-salt intake. To this end male Sprague-Dawley rats were fed a low-salt diet (0.2 mg/g) for 10 days and were treated with the ANGII-AT₁ receptor antagonist losartan (40 mg/kg per day) for 2 days, and adrenal mRNA levels for ANGII AT_1A and AT_1B receptors were determined by RNase protection. The low-salt diet increased AT_1A and AT_1B receptor mRNA levels by 90% and 220%, respectively. Losartan treatment did not change the basal AT_1A mRNA level, but decreased AT_1B mRNA by 50%. Treatment of rats on a low-salt diet with losartan did not change the increase of AT_1A mRNA but significantly attenuated the increase of AT_1B mRNA to 90% of the control value. Stimulation of endogenous ANGII levels by unilateral renal artery clipping for 2 days lowered AT_1A mRNA by 25% and increased AT_1B mRNA by 30%. Additional treatment with losartan did not affect the decreased AT_1A mRNA levels in rats with a unilateral renal artery clip, but significantly attenuated the increase of AT_1B mRNA. These findings suggest that sodium deficiency stimulates adrenal AT_1A and AT_1B receptor mRNA levels primarily via an ANGII-AT₁-independent mechanism. The preferential increase of adrenal AT_1B mRNA during a low-salt intake could be explained by the elevation of endogenous ANGII levels during sodium deficiency, suggesting that endogenous ANGII acts as an enhancer for adrenal AT_1B but not for AT_1A receptor gene expression via ANGII-AT₁ receptors. Received: 23 May 1997 / Received after revision: 23 February 1998 / Accepted: 11 March 1998     

老年大鼠肾脏微分离肾小球、肾小管及动脉血管紧张素Ⅱ受体的表达

目的: 观察老年大鼠肾脏不同部位不同亚型的血管紧张素Ⅱ受体(ATR)基因表达的改变。方法: 取3月龄及24月龄雄性Wistar大鼠肾脏,行Western印迹杂交及Northern 印迹杂交检测肾皮质AT₁R的蛋白及基因表达,行冰冻切片(厚5 μm),通过激光切割、弹射微分离系统分离肾小球、肾小管及动脉,提取RNA,利用RT-PCR方法观察AT_1aR mRNA、AT_1bR mRNA及AT₂R mRNA的表达。结果: 24月龄大鼠肾脏的AT₁R在蛋白水平及基因水平均低于3月龄大鼠。应用自动激光微分离技术成功分离了大鼠肾脏的肾小球、肾小管及小动脉。24月龄大鼠肾小球AT_1aR mRNA的表达与3月龄大鼠比较无明显差异,在肾小管表达低于3月龄大鼠,动脉表达高于3月龄大鼠;AT_1bR mRNA在肾小球、肾小管表达均低于3月龄大鼠,在动脉的表达高于3月龄大鼠;AT₂R mRNA的表达在肾小管明显高于3月龄大鼠,在肾小球及动脉的表达无明显差异。结论: 老年大鼠的肾小球、肾小管及肾内动脉各型血管紧张素受体的改变不同,有可能在肾脏增龄性改变中起重要作用。     

Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats

Aims: G protein‐coupled receptors such as the AT_1aR are frequently subject to desensitization, extensively studied in cell culture but to small extent in hypertensive models. Recently, angiotensin II (ANG II)‐induced desensitization was shown to last 10 min in isolated afferent arterioles (AAs), suggesting impact on ANG II vasoactivity. In the present study, we explored ANG II desensitization and effects of adenosine (Ado) in AAs from two‐kidney, one‐clip (2K1C) hypertensive rats. Our main hypothesis was that Ado affects ANG II contractility differently in 2K1C, because of persistently elevated levels of ANG II. Methods: Afferent arterioles were isolated with the agarose‐infusion/enzyme‐treatment technique from normotensive and 2K1C hypertensive rats, and stimulated with ANG II (10^?7 m ) at baseline and re‐stimulated after 20 or 40 min, with or without Ado (2.5 × 10^?5 m ) in the vessel bath. Results: Afferent arterioles from normotensive rats re‐stimulated with ANG II after 20 min displayed a blunted contraction (Δ12.8 ± 4.3%, P < 0.05), which disappeared when AAs were stimulated after 40 min (Δ2.7 ± 2.3%, NS), indicating that desensitization lasted for 30 ± 10 min. Ado augmented ANG II contractions after 20 min, but not after 40 min, suggesting that only de‐sensitized vessels were affected. Similar experiments in AAs from the clipped and non‐clipped kidneys revealed no desensitization when re‐stimulated with ANG II after 20 and 40 min, and contractions were unaffected by Ado. Conclusions: Reduced duration of desensitization in AAs from 2K1C may cause vessels to be sensitized longer and increase vasoconstriction. The present study demonstrates that Ado does not augment ANG II‐induced contractions in AAs from 2K1C as in normotensive rats, possibly because of a reduced period of desensitization.     

Alteration of embryonic AT2-R and inflammatory cytokines gene expression induced by prenatal exposure to lipopolysaccharide affects renal development

Prenatal exposure to LPS(lipopolysaccharide) results in renal damage in offspring rats, but the mechanism is unknown. The present study was to explore the role of angiotensin II and inflammation in the development of renal damage induced by prenatal exposure to LPS. The pregnant rats were randomly divided into two groups, i.e., control group, LPS group. The rats in the two groups were administered intraperitoneally with vehicle or 0.79 mg/kg LPS on 8th, 10th and 12th day during gestation. The mRNA expression of angiotensinogen, renin, AT₁-R, AT₂-R, TNF-α and IL-6 in embryos were assessed. Renal Ang II-positive cells, monocytes/macrophages, lymphocytes, collagen I and TUNEL-positive cells were identified by immunohistochemical staining in newborn and 7-week-old offspring rats. The number of glomeruli and creatinine clearance rate were determined in offspring at 7 weeks of age. The results showed that prenatal LPS decreased AT₂-R mRNA expression but increased TNF-α and IL-6 mRNA expression in embryos. Prenatal LPS decreased renal angiotensin II-positive cells in newborn offspring rats, while these increased in 7-week-old offspring rats. Prenatal LPS decreased glomerular number and creatinine clearance rate but increased renal infiltrating monocytes/macrophages and lymphocytes at 7 weeks of age. Prenatal LPS also increased TUNEL-positive cells and collagen I expressions in newborn rats and 7-week-old offspring rats.ConclusionAlteration of embryonic AT₂-R and inflammatory cytokines gene expression induced by prenatal exposure to lipopolysaccharide affects renal development.     

AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function

The renin–angiotensin system (RAS) is a coordinated hormonal cascade intimately involved in cardiovascular and renal control and blood pressure regulation. Angiotensin II (Ang II), the major RAS effector peptide, binds two distinct receptors, the angiotensin type-1 receptor (AT₁R) and the angiotensin type-2 (AT₂R) receptor. The vast majority of the physiological actions of Ang II, almost all of them detrimental, are mediated by AT₁Rs. In contrast, AT₂Rs negatively modulate the actions of AT₁Rs under the majority of circumstances and generally possess beneficial effects. AT₂Rs induce vasodilation in both resistance and capacitance vessels, mediating natriuresis directly and via interactions with dopamine D1 receptors in the renal proximal tubule. AT₂Rs inhibit renin biosynthesis and secretion and protect the kidneys from inflammation and ischemic injury. Our understanding of the exact role of AT₂Rs in physiology and pathophysiology continues to expand; the purpose of this review is to provide an up-to-date summary of the functional role of AT₂Rs at the organ, tissue, cellular, and subcellular levels with emphasis on the vascular and renal actions that bear on blood pressure regulation and hypertension.     

Evolving concepts on regulation and function of renin in distal nephron

Sustained stimulation of the intrarenal/intratubular renin–angiotensin system in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis, and eventual renal injury. Activation of luminal AT₁ receptors in proximal and distal nephron segments by local Ang II formation stimulates various transport systems. Augmented angiotensinogen (AGT) production by proximal tubule cells increases AGT secretion contributing to increased proximal Ang II levels and leading to spillover of AGT into the distal nephron segments, as reflected by increased urinary AGT excretion. The increased distal delivery of AGT provides substrate for renin, which is expressed in principal cells of the collecting tubule and collecting ducts, and is also stimulated by AT₁ receptor activation. Renin and prorenin are secreted into the tubular lumen and act on the AGT delivered from the proximal tubule to form more Ang I. The catalytic actions of renin and or prorenin may be enhanced by binding to prorenin receptors on the intercalated cells or soluble prorenin receptor secreted into the tubular fluid. There is also increased luminal angiotensin converting enzyme in collecting ducts facilitating Ang II formation leading to stimulation of sodium reabsorption via sodium channel and sodium/chloride co-transporter. Thus, increased collecting duct renin contributes to Ang II-dependent hypertension by augmenting distal nephron intratubular Ang II formation leading to sustained stimulation of sodium reabsorption and progression of hypertension.     

Endothelium derived relaxing factor is involved in the pressure control of renin gene expression in the kidney

To study the influence of endothelium derived relaxing factor/nitric oxide (EDNO) on renin gene expression, the effects of a 2-day treatment with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg twice a day) on plasma renin activity (PRA) and renal and adrenal renin m-RNA levels were examined in conscious rats with and without unilateral renal clips (0.2 mm). In sham-clipped animalsL-NAME led to a decrease of PRA from 7.5 to 2.5 ng angiotensin I (ANGI) · h^–1 · ml^–1 and to a 35% decrease of renal renin m-RNA levels. Unilateral renal artery clipping increased PRA to 35 and to 13 ng ANGI · h^–1 · ml^–1 in vehicle and inL-NAME-treated rats, respectively. In the clipped kidneys renin m-RNA levels increased to 450% of control values in vehicle-treated animals and to 220% of control values inL-NAME-treated animals. In the contralaterals as opposed to clipped kidneys, renin m-RNA levels decreased to 16% and 50% of the control values in vehicle- and inL-NAME-treated animals, respectively. In the adrenal glands renin m-RNA levels were not significantly changed either by clipping of one renal artery or by treatment of animals withL-NAME. The NO-donor sodium nitroprusside (100 M) was found to increase renin secretion and renin m-RNA levels in primary cultures of renal juxtaglomerular cells. These findings suggest that EDNO is involved in the control of the renin gene by the renal perfusion pressure.     

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs

Experiments were carried out to investigate age- and dose-dependent effects of the selective AT₁ receptor antagonist, ZD 7155, and the selective AT₂ receptor antagonist, PD 123319, on systemic and renal hemodynamics in conscious, chronically instrumented lambs aged ∼1 and ∼6 weeks of postnatal life. Mean arterial pressure (MAP), mean venous pressure (MVP), and renal blood flow (RBF) were measured for 10 min before and for 120 min after ZD 7155, PD 123319, or vehicle. In both age groups, administration of ZD 7155 decreased renal vascular resistance (RVR) and increased RBF within 5 min. These responses lasted less than 90 min but were not dose-dependent. MAP decreased by 30 min after administration of ZD 7155 in both age groups at doses ≥400 μg kg⁻¹; the remaining decreased for up to 120 min, depending upon the dose. Pressor responses to angiotensin II (ANG II) were abolished within 5 min of administration of all doses of ZD 7155, at both 1- and 6 weeks. PD 123319 had no detectable effects on systemic or renal hemodynamics or on the pressor responses to ANG II. Therefore, under physiological conditions in conscious newborn animals, ANG II modulates both resting blood pressure and RVR through activation of AT₁ but not AT₂ receptors.     

Expression of angiotensin II and its receptors in the normal and hypoxic amoeboid microglial cells and murine BV-2 cells

Involvement of the local angiotensin receptor system in the central nervous system is well documented, yet its cellular localization and role in the glial cells have remained elusive. This study reports expression of angiotensin II and its receptors namely, angiotensin II receptor type 1 (AT₁) and angiotensin II receptor type 2 (AT₂) in the amoeboid microglial cells in the neonatal rat brain. In rats subjected to hypoxia, the amount of angiotensin II released in the corpus callosal tissue was reduced as revealed by enzyme immunoassay. Expression of AT₁ mRNA and protein was down-regulated after hypoxic exposure, but AT₂ was up-regulated. In BV-2 cells exposed to hypoxia for 4 h, expression of AT₁ mRNA was reduced but AT₂ was increased. These changes were further intensified respectively in LPS-stimulated microglia. Edaravone enhanced AT₁ expression but suppressed AT₂ expression significantly in lipopolysaccharide-stimulated cells. Neutralization of AT₂ with its antiserum significantly increased mRNA expression of tumor necrosis factor-α and interleukin-1β but decreased that of transforming growth factor-beta1. In conclusion, the present results suggest that AT₁ may be linked to regulation of vasodilation for increase of blood flow in hypoxic conditions, while up-regulated expression of AT₂ may reduce inflammatory responses through suppression of proinflammatory cytokines and elimination of free radicals.     

Inhibition of PKC-dependent extracellular Ca2+ entry contributes to the depression of contractile activity in long-term pressure-overloaded endothelium-denuded rat aortas

We examined the contractile responsiveness of rat thoracic aortas under pressure overload after long-term suprarenal abdominal aortic coarctation (lt-Srac). Endothelium-dependent angiotensin II (ANG II) type 2 receptor (AT₂R)-mediated depression of contractions to ANG II has been reported in short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG I and II levels and AT₂R protein expression in the aortas of lt-Srac and Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac did not influence the transient contractions induced in endothelium-denuded aortic rings by ANG II, phenylephrine, or caffeine in Ca²⁺-free medium or the subsequent tonic constrictions induced by the addition of Ca²⁺ in the absence of agonists. Thus, the contractions induced by Ca²⁺ release from intracellular stores and Ca²⁺ influx through stored-operated channels were not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with control tissues. Consequently, the contractile depression observed in aortic tissues of lt-Srac rats cannot be explained by direct inhibition of voltage-operated Ca²⁺ channels. Interestingly, 12-O-tetradecanoylphorbol-13-acetate-induced contractions in endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but not in the absence of extracellular Ca²⁺. Neither levels of angiotensins nor of AT₂R were modified in the aortas after lt-Srac. The results suggest that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated activation of contraction that is dependent on extracellular Ca²⁺ entry.     

Influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of rats

The aim of this study was to examine the influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of adult rats. Rats were kept on low (0.02%, w/w), normal (0.6%) or high (4%) NaCl diets and plasma renin activity (PRA) and the relative abundance of renin messenger ribonucleic acid (mRNA) in renal and adrenal tissue were followed for 20 days. In animals on a normal-salt diet PRA and renal renin mRNA levels did not change with time. PRA values in animals on the low-salt diet increased transiently (about threefold) and then declined again during the third week of treatment. Renal renin mRNA levels in these animals paralleled the changes of PRA. Conversely, in the animals kept on a high-salt diet PRA values decreased transiently and renal renin mRNA decreased continuously to about 50% of control values. Arterial blood pressure measured in conscious animals was not significantly influenced by the different salt diets. To establish whether the changes in renin mRNA levels are mediated by renal nerve input, animals on the different diets were also studied after unilateral renal denervation. Renal nerve section led to a 50% decrease of renin mRNA levels in the denervated kidneys in animals kept on the normal-salt diet. In the animals on the low-salt diet renin mRNA rose to similar levels in the denervated to those in the innervated kidney, while in animals receiving a high-salt diet renin mRNA was further decreased in the denervated kidneys. The abundance of renin mRNA in adrenal tissue was low and was estimated to be around 1% of that found in the kidneys. Adrenal renin mRNA levels also increased in animals kept on a low-salt diet and decreased in animals on high-salt diet. Taken together, our findings suggest that renin secretion and renin gene expression are inversely related to salt intake and that the influence of salt diet on these parameters has both transient and constant temporal components. Changes of blood pressure or nerve activity are not likely mediators of the effect of salt intake on renin expression. Since renal and adrenal renin mRNA levels change in parallel in response to alterations of salt intake we hypothesize the existence of a humoral factor that links renin expression to the rate of salt intake.     

The renin–angiotensin system in kidney development

All components of the renin–angiotensin system (RAS) are highly expressed in the developing kidney in a pattern suggesting a role for angiotensin II in renal development. In support of this notion, pharmacological interruption of angiotensin II type‐1 (AT₁) receptor signalling in animals with an ongoing nephrogenesis produces specific renal abnormalities characterized by papillary atrophy, abnormal wall thickening of intrarenal arterioles, tubular atrophy associated with expansion of the interstitium, and a marked impairment in urinary concentrating ability. Similar changes in renal morphology and function develop also in mice with targeted inactivation of genes encoding renin, angiotensinogen, angiotensin‐converting enzyme, or both AT₁ receptor isoforms simultaneously. Taken together, these results clearly indicate that an intact signalling through AT₁ receptors is a prerequisite for normal renal development. The present report mainly reviews the renal abnormalities induced by blocking the RAS pharmacologically in experimental animal models. In addition, pathogenetic mechanisms are discussed.     

Angiotensin receptors as determinants of life span

Angiotensin II (Ang II), the central product of renin-angiotensin system, has a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT₁). Several experimental studies have demonstrated that Ang II acts through AT₁ as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT_1A) in mice translates into marked prolongation of life span. The absence of AT_1A protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT₁ receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT₁ pathway represents a feasible therapeutic strategy to prolong life span in humans.     

AT1 receptor up-regulation in intestine in chronic renal failure is segment specific

 The role of the AT₁ receptor in stimulating colonic K⁺ secretion was investigated in rats with chronic renal failure (CRF) induced by 5/6 nephrectomy. Compared to control rats, CRF rats up-regulate mucosal AT₁ receptors approximately two-fold in the proximal (PC) and distal (DC) colonic segments. In contrast, there was no alteration in AT₁ receptor protein mass in jejunal or ileal mucosa. Using ⁸⁶Rb⁺ as a tracer for transmural K⁺ fluxes, a significant stimulation of the basal K⁺ secretory flux across both PC and DC was observed in vitro and this alteration in K⁺ transport was temporally correlated with the increase in angiotensin II (ANG II) receptors. In both PC and DC the significant increases in the receptor protein were evident 48 h after partial nephrectomy and they were sustained through 6 weeks. These studies support the hypothesis that CRF-induced secretion of K⁺ is mediated by an up-regulation of AT₁ receptors exclusively in the large intestinal segments. Received: 14 October 1998 / Received after revision: 12 December 1998 / Accepted: 21 December 1998