Involvement of an enterocyte renin–angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane

There is increasing evidence that locally produced angiotensin AII (AII) regulates the function of many tissues, but the involvement of enterocyte-derived AII in the control of intestinal transport is unknown. This study examined whether there is a local renin–angiotensin system (RAS) in rat villus enterocytes and assessed the effects of AII on SGLT1-dependent glucose transport across the brush border membrane (BBM). Gene and protein expression of angiotensinogen, ACE, and AT₁ and AT₂ receptors were studied in jejunal and ileal enterocytes using immunocytochemistry, Western blotting and RT-PCR. Mucosal uptake of d -[¹⁴C]glucose by everted intestinal sleeves before and after addition of AII (0–100 n m ) to the mucosal buffer was measured in the presence or absence of the AT₁ receptor antagonist losartan (1 μ m ). Immunocytochemistry revealed the expression of angiotensinogen, ACE, and AT₁ and AT₂ receptors in enterocytes; immunoreactivity of AT₁ receptor and angiotensinogen proteins was especially pronounced at the BBM. Expression of angiotensinogen and AT₁ and AT₂ receptors, but not ACE, was greater in the ileum than the jejunum. Addition of AII to mucosal buffer inhibited phlorizin-sensitive (SGLT1-dependent) jejunal glucose uptake in a rapid and dose-dependent manner and reduced the expression of SGLT1 at the BBM. Losartan attenuated the inhibitory action of AII on glucose uptake. AII did not affect jejunal uptake of l -leucine. The detection of RAS components at the enterocyte BBM, and the rapid inhibition of SGLT1-dependent glucose uptake by luminal AII suggest that AII secretion exerts autocrine control of intestinal glucose transport.     

Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity

Recent studies have demonstrated the presence of the (pro)renin receptor (PRR) in the glomerular mesangium and the subendothelial layer of the renal arteries. We hypothesized that diabetes upregulates PRR expression through enhanced angiotensin subtype 1 (AT₁) receptor–NADPH oxidase cascade activity. Using real-time polymerase chain reaction, Western blot analysis and immunostaining, we studied renal localization of the PRR in the streptozotocin-induced diabetic rat model and in response to 1 week of treatment with the AT₁ receptor blocker valsartan (10 mg kg⁻¹ day⁻¹), the angiotensin AT₂ receptor blocker PD123319 (0.5 mg kg⁻¹ day⁻¹) or the NADPH oxidase inhibitor diphenylene iodonium (DPI; 0.5 mg kg⁻¹ day⁻¹) 6 weeks post-induction of diabetes. Both PRR mRNA and protein were expressed constitutively in the kidneys of normal rat renal cortex and medulla, mainly in glomerular mesangium, proximal, distal and collecting tubules. Compared with normal rats (100%), diabetic rats demonstrated an increase in renal PRR mRNA (184%), protein (228%) and immunostaining. Valsartan and DPI prevented the increase in the PRR mRNA (106 and 126%, respectively), protein (97 and 140%, respectively) and immunostaining that was seen in the kidneys of diabetic rats. The AT₂ blocker PD123319 did not have significant effects on PRR mRNA (157%) or protein expression (200%) in the kidneys of diabetic rats. These results demonstrate that the PRR is constitutively expressed in renal glomeruli and tubules. Expression of the PRR is upregulated in diabetes via enhancement of AT₁ receptor–NADPH oxidase activity.     

Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep

Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT₁) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular ( i.c.v. ) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h⁻¹; n = 7), CORT (5 mg h⁻¹, n = 6) or SAL ( n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 μg h⁻¹) were significantly greater in the DEX group (10 ± 1 mmHg at 1 μg h⁻¹) compared with SAL (6 ± 1 mmHg) or CORT (6 ± 1 mmHg) animals ( P < 0.05). i.c.v. infusion of the AT₁ antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT₁ receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.     

Increased glomerular angiotensin II binding in rats exposed to a maternal low protein diet in utero

In the rat, protein restriction during pregnancy increases offspring blood pressure by 20–30 mmHg. We have shown in an earlier study that this is associated with a reduction in nephron number and increased glomerular sensitivity to angiotensin II (Ang II) in vivo . Hence, we hypothesized that exposure to a maternal low-protein diet increases glomerular Ang II AT₁ receptor expression and decreases AT₂ receptor expression. To test this hypothesis, pregnant Wistar rats were fed isocalorific diets containing either 18% (control) or 9% (LP) protein from conception until birth. At 4 weeks of age, the kidneys of male offspring were harvested to measure cortical AT₁ and AT₂ receptor expression, ¹²⁵I-Ang II glomerular binding, tissue renin activity, tissue Ang II and plasma aldosterone concentrations. AT₁ receptor expression was increased (62%) and AT₂ expression was decreased (35%) in LP rats. Maximum ¹²⁵I-Ang II (¹²⁵I-Ang II) binding ( B _max) was increased in LP rats (control n = 9, 291.6 ± 27.4 versus LP n = 7, 445.7 ± 27.4 fmol (mg glomerular protein)⁻¹, P < 0.01), but affinity ( K _D) was not statistically different from controls (control 2.87 ± 0.85 versus LP 0.84 ± 0.20 pmol ¹²⁵I-Ang II, P = 0.059). Renal renin activity, tissue Ang II and plasma aldosterone concentrations did not differ between control and LP rats. Increased AT₁ receptor expression in LP rat kidneys is consistent with greater haemodynamic sensitivity to Ang II in vivo . This may result in an inappropriate reduction in glomerular filtration rate, salt and water retention, and an increase in blood pressure.     

Prenatal corticosterone exposure results in altered AT1/AT2, nephron deficit and hypertension in the rat offspring

Maternal treatment with the synthetic glucocorticoid, dexamethasone has been reported to result in a nephron deficit and development of hypertension in the offspring of rats. However, it is not known whether elevated maternal corticosterone (CORT), the natural glucocorticoid, has similar effects on blood pressure and nephron endowment. The present study investigated the effects of CORT (0.8 mg kg⁻¹ day⁻¹) administration on embryonic day 14 (E14) and E15 of pregnancy on: (1) nephron number at postnatal day 30 (PN30); (2) blood pressure at PN120; and (3) receptors of the renal renin–angiotensin system (RRAS) (AT₁Ra, AT₁Rb and AT₂Ra) during both embryonic (E16, E20) and adolescent (PN30) life. Plasma CORT concentrations were approximately doubled 30 min after injection. Unbiased stereological analysis revealed that maternal CORT treatment resulted in a nephron deficit of 21 and 19% in male and female offspring, respectively. Mean arterial pressures were significantly elevated in offspring of both sexes from the CORT group. Real-time PCR revealed that CORT treatment increased expression of AT₁Ra and AT₂R at E16, and at PN30. Expression of AT₁Rb was downregulated in embryonic life but upregulated at PN30. We believe that these results are the first to demonstrate that maternal CORT treatment results in a nephron deficit and development of hypertension in the rat offspring. Changes in the RRAS may be contributing to these phenotypes. Critically, this study suggests that increased but physiological levels of the natural glucocorticoid can programme similar changes to those seen with pharmacological doses of the synthetic glucocorticoid. This may have important implications for women experiencing significant stress during pregnancy.     

Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats

The renal medulla is sensitive to hypoxia, and a depression of medullary circulation, e.g. in response to angiotensin II (Ang II), could endanger the function of this zone. Earlier data on Ang II effects on medullary vasculature were contradictory. The effects of Ang II on total renal blood flow (RBF), and cortical and medullary blood flow (CBF and MBF: by laser-Doppler flux) were studied in anaesthetised rats. Ang II infusion (30 ng kg⁻¹ min⁻¹ i.v. ) decreased RBF 27 ± 2 % (mean ± s.e.m. ), whereas MBF increased 12 ± 2 % (both P < 0.001). Non-selective blockade of Ang II receptors with saralasin (3 μg kg⁻¹ min⁻¹ i.v. ) increased RBF 12 ± 2 % and decreased MBF 8 ± 2 % ( P < 0.001). Blockade of AT₁ receptors with losartan (10 mg kg⁻¹) increased CBF 10 ± 2 % ( P < 0.002) and did not change MBF. Losartan given during Ang II infusion significantly increased RBF (53 ± 7 %) and decreased MBF (27 ± 7 %). Blockade of AT₂ receptors with PD 123319 (50 μg kg⁻¹ min⁻¹ i.v. ) did not change CBF or MBF. Intramedullary infusion of PD 123319 (10 μg min⁻¹) superimposed on intravenous Ang II infusion did not change RBF, but slightly decreased MBF (4 ± 2 %, P < 0.05). We conclude that in anaesthetised surgically prepared rats, exogenous or endogenous Ang II may not depress medullary circulation. In contrast to the usual vasoconstriction in the cortex, vasodilatation was observed, possibly related to secondary activation of vasodilator paracrine agents rather than to a direct action via AT₂ receptors.     

Involvement of Src tyrosine kinase and mitogen-activated protein kinase in the facilitation of calcium channels in rat nucleus of the tractus solitarius by angiotensin II

It is recognized that brain contains all the components of the renin–angiotensin systems (RAS). The nucleus of the tractus solitarius (NTS) is known to play a major role in the regulation of cardiovascular, respiratory, gustatory, hepatic and swallowing functions. Voltage-dependent Ca²⁺ channels (VDCCs) serve as crucial mediators of membrane excitability and Ca²⁺-dependent functions such as neurotransmitter release, enzyme activity and gene expression. The purpose of this study was to investigate the effects of angiotensin II (Ang II) on VDCC currents ( I _Ca) in the NTS using patch-clamp recording methods. An application of Ang II caused facilitation of L-type I _Ca in a concentration-dependent manner with an EC₅₀ of 167 n m and a Hill coefficient of 1.73. AT₁ receptor antagonist losartan antagonized the Ang II-induced facilitation of I _Ca. Intracellular dialysis of the Gα_i-protein antibody attenuated the Ang II-induced facilitation of I _Ca. Both Src tyrosine kinase inhibitor and mitogen-activated protein kinase (MAPK) inhibitor attenuated the Ang II-induced facilitation of I _Ca. p38 MAPK inhibitor also attenuated the Ang II-induced facilitation of I _Ca. These results indicate that Ang II facilitates L-type VDCCs via Gα_i-proteins involving Src tyrosine kinase and p38 MAPK kinase mediated by AT₁ receptors in NTS.     

The angiotensin receptor type 1-Gq protein-phosphatidyl inositol phospholipase Cbeta-protein kinase C pathway is involved in activation of proximal tubule Na+-ATPase activity by angiotensin(1-7) in pig kidneys

In a previous study, we observed that angiotensin(1–7) (Ang(1–7)) stimulates proximal tubule Na⁺-ATPase activity through the angiotensin receptor type 1 (AT₁R). Here we aimed to study the signalling pathways involved. Our results show that the stimulatory effect of Ang(1–7) on Na⁺-ATPase activity through AT₁R involves a G_q protein–phosphatidyl inositol-phospholipase Cβ(PI-PLCβ) pathway because: (1) the effect was reversed by GDPβS, a non-hydrolysable GDP analogue, and by a monoclonal G_q protein antibody; (2) the effect was similar and not additive to that of GTPγS, a non-hydrolysable GTP analogue; (3) Ang(1–7) induced a rapid decrease (30 s) in phosphatidylinositol 4,5-bisphosphate levels, a PI-PLCβ substrate; and (4) U73122, a specific inhibitor of PI-PLCβ, abolished Ang(1–7)-induced stimulation of Na⁺-ATPase activity. Angiotensin(1–7) increased the protein kinase C (PKC) activity similarly to phorbol-12-myristate-13-acetate (PMA), an activator of PKC. This effect was reversed by losartan, a specific antagonist of AT₁R. The stimulatory effects of Ang(1–7) and PMA on Na⁺-ATPase activity are similar, non-additive and reversed by calphostin C, a specific inhibitor of PKC. A catalytic subunit of PKC (PKC-M) increased the Na⁺-ATPase activity. These data show that Ang(1–7) stimulates Na⁺-ATPase activity through the AT₁R–G_q protein–PI-PLCβ–PKC pathway. This effect is similar to that described for angiotensin II, showing for the first time that these compounds could have similar effects in the renal system.     

Interleukin-6 is essential for Staphylococcal exotoxin B-induced T regulatory cell insufficiency in nasal polyps

Background The pathogenesis of nasal polyps is still unclear. There is increasing evidence indicating that Staphylococcal aureus (S. aureus) is associated with the formation of nasal polyps, but the mechanism has not been well documented to date.
Methods We stimulated cultured nasal polyps and turbinate tissues with Staphylococcal exotoxin B (SEB), detected the expression of pro-inflammatory cytokines (IL-2, IL-6, and IL-8) and T cell cytokines (IFN-γ, IL-4, IL-5, IL-10, and IL-17) in the supernatants, and evaluated mRNA expression (T-bet, GATA-3, Foxp3, and RORγt) and frequencies of CD4⁺CD25⁺ T regulatory cells (Tregs) in nasal tissues. We also evaluated the effects of blocking IL-6 with monoclonal antibodies to T cell profiles in cultured nasal tissues stimulated by SEB.
Results Levels of IL-6, IFN-γ and IL-4 increased significantly in SEB-stimulated nasal polyps. Meanwhile, mRNA expressions of T-bet and GATA-3 were significantly up-regulated, while Foxp3 was inhibited and the frequencies of CD4⁺CD25⁺ Tregs were decreased after SEB stimulation. After blocking IL-6, the levels of IL-10 and Foxp3 mRNA, as well as the frequencies of CD4⁺CD25⁺ Tregs, were significantly increased, while IFN-γ and IL-4 production and the mRNA expression of T-bet and GATA-3 were significantly inhibited.
Conclusions SEB is able to modulate pro-inflammatory factors, T-helper type 1/Th2 profiles and suppress Treg activity in cultured nasal polyps, which were rescued by blocking IL-6 activity. Therefore, IL-6 is essential for SEB-induced Treg insufficiency in nasal polyps.     

The decrease in mature myostatin protein in male skeletal muscle is developmentally regulated by growth hormone

Myostatin inhibits myogenesis and there is reduced abundance of the mature protein in skeletal muscles of adult male compared with female mice. This reduction probably occurs after translation, which suggests that it is a regulated mechanism to reduce the availability of myostatin in males. Reduced myostatin may, thereby, contribute to the development of sexually dimorphic growth of skeletal muscle. Our first objective was to determine if the decrease in mature myostatin protein occurs before the linear growth phase to aid growth, or afterwards to maintain the mass of adult muscle. Mice were killed from 2 to 32 weeks and the gastrocnemius muscle was excised. Myostatin mRNA increased from 2 to 32 weeks and was higher in males than females ( P < 0.001). In contrast, mature protein decreased in males after 6 weeks ( P < 0.001). Our second objective was to determine if growth hormone (GH) induces the decrease in mature myostatin protein. GH increased myostatin mRNA and decreased the abundance of mature protein in hypophysectomised mice ( P < 0.05). Our final objective was to determine if the decrease in mature protein occurs in skeletal muscles of male Stat5b ^−/− mice (Stat5b mediates the actions of GH). As expected, mature myostatin protein was not reduced in Stat5b ^−/− males compared with females. However, myostatin mRNA remained higher in males than females irrespective of genotype. These data suggest that: (1) the decrease in mature myostatin protein is developmentally regulated, (2) GH acting via Stat5b regulates the abundance of mature myostatin and (3) GH acts via a non-Stat5b pathway to regulate myostatin mRNA.     

Effects of placental insufficiency on the ovine fetal renin-angiotensin system

We postulated that chronic placental insufficiency would be associated with reduced expression of renal renin and angiotensinogen genes in the fetal sheep. Placental development was restricted in ewes by removing the majority of caruncles prior to mating (placentally restricted (PR) group). The weights of PR fetuses were significantly reduced (P < 0.05, 2.98 +/- 0.33 kg) compared to control fetuses (4.20 +/- 0.30 kg). Kidney weights were also significantly reduced in the PR fetuses (P < 0.05, 8.4 +/- 0.9 g) compared with control fetuses (12.2 +/- 1.3 g). The ratios of renal renin/-actin mRNA levels were significantly reduced in PR fetuses (P < 0.001, 0.35 +/- 0.02) when compared to control animals (0.98 +/- 0.13). The renal angiotensinogen mRNA/18S rRNA ratio was significantly lower (P < 0.05, 0.28 +/- 0.13) in PR fetuses compared with control fetuses (0.72 +/- 0.10), while hepatic angiotensinogen was unaffected. There was a positive correlation between renal renin mRNA and renal angiotensinogen mRNA levels (r = 0.65, P < 0.05, n = 12). It is unlikely that these changes in renal angiotensinogen and renin mRNA were due to the small increment in plasma cortisol levels (< 5 nmol l-1). There was, however, a positive correlation between arterial PO2 and renal renin mRNA (r2 = 0.77, P < 0.01). Plasma renin levels were not different between the two groups. Thus, restriction of nutrient and oxygen supply throughout fetal life was associated with suppression of renal renin and renal angiotensinogen gene expression, with no effect on hepatic angiotensinogen mRNA levels. This specific suppression of fetal renal renin and angiotensinogen expression could alter the activity of the intrarenal RAS and so affect growth and development of the kidney.     

Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats

Sympathetic outflow is increased in hypertension. The aim of the present study was to investigate whether the cardiac sympathetic afferent reflex (CSAR) is enhanced in two-kidney one-clip (2K1C) renovascular hypertensive rats, and whether the enhanced CSAR contributes, in part, to the increased sympathetic outflow. Furthermore, the role of central angiotensin II type 1 (AT₁) receptors in mediating the CSAR was determined. Under urethane and α-chloralose anaesthesia, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic denervated and cervical vagotomized rats. The CSAR was evaluated by the response of RSNA and MAP to epicardial application of 1.0 nmol of capsaicin. Compared with sham-operated rats, the CSAR, baseline RSNA and plasma noradrenaline level were significantly enhanced in 2K1C rats. Intrapericardial administration of resiniferatoxin, which abolishes the CSAR because of the desensitization of transient receptor potential vanilloid 1-containing cardiac afferent fibres, decreased the RSNA and MAP. The enhanced CSAR in 2K1C rats was normalized by intracerebroventricular administration of the AT₁ receptor antagonist losartan. Intracerebroventricular administration of angiotensin II further potentiated the enhanced CSAR in 2K1C rats, a response which was abolished by pretreatment with losartan. These results indicate that the CSAR is enhanced in 2K1C rats and the enhanced CSAR contributes, in part, to the sympathetic activation and hypertension. Central AT₁ receptors are involved in the enhanced CSAR in 2K1C rats.     

高果糖膳食对大鼠脂肪组织肾素-血管紧张素系统的影响

目的:观察高果糖膳食对大鼠脂肪组织炎症及肾素-血管紧张素系统(renin-angiotensin system,RAS)的影响,探讨Toll样受体2(Toll-like receptor 2,TLR2)炎症信号通路在其中的作用。方法:16只SPF级雄性SD大鼠随机分为正常对照组、高果糖组、高果糖+si RNA阴性对照组及高果糖+TLR2-siRNA组,正常对照组以普通饲料喂养,高果糖组以含60%果糖饲料喂养,高果糖+TLR2-siRNA组和高果糖+si RNA阴性对照组大鼠另分别予以TLR2-siRNA和si RNA阴性对照转染。干预14周后,检测大鼠血尿酸水平,ELISA法检测血清白细胞介素6(interleukin-6,IL-6)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、血管紧张素原(angiotensinogen,AGT)和血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)的水平,称取腹部脂肪重量,免疫组化法检测脂肪组织巨噬细胞的浸润,realtime PCR法检测脂肪组织IL-6、TNF-α、单核细胞趋化蛋白1(monocyte chemoattractant protein-1,MCP-1)、AGT、血管紧张素转化酶1(angiotensin-converting enzyme 1,ACE1)、血管紧张素Ⅱ1型受体(angiotensinⅡtype 1 receptor,AT1R)和血管紧张素Ⅱ2型受体(angiotensinⅡtype 2 receptor,AT2R) m RNA表达,Western blot检测TLR2的蛋白表达。结果:与正常对照组比较,高果糖组大鼠血尿酸明显升高,腹部脂肪重量明显增加,血清IL-6、TNF-α、AGT和AngⅡ水平明显升高,脂肪组织巨噬细胞浸润数量明显增多,脂肪组织IL-6、TNF-α、MCP-1、AGT、ACE1、AT1R和AT2R的m RNA水平明显升高(P 0. 05);与高果糖组比较,高果糖+TLR2-siRNA组大鼠血尿酸及腹部脂肪重量无明显变化,TLR2蛋白表达显著减低,血清及脂肪组织炎症因子的m RNA水平显著降低,脂肪组织巨噬细胞浸润数量明显减少,血清AGT、AngⅡ及脂肪组织RAS信号通路相关因子的m RNA水平明显下调(P 0. 05)。结论:高果糖膳食上调脂肪组织RAS,其机制可能与TLR2炎症信号通路激活相关。     

Cytokine Gene Expression During Infeetion of Miee Lacking CD4 and/or CD8 with Trypanosoma cruzi

The expression of lymphokine genes during infection of virulent (Tulahuén) or mild ( CA-I ) strains of T. cruzi was studied in mice lacking CD4 and/or CD8 molecules. The increased susceptibility of CD4⁻ and CD4⁻ CD8⁻ mice to infection with CA-I or Tuiahuen was parallelled by diminished IFN-γ mRNA levels. Nitric oxide release and inducible nitric oxide synthase mRNA accumulation by cells from Tulahuen infected CD4⁻ mice was also diminished. CD8⁻ (but not CD4⁻ CD8⁻ mice) showed an increased IL-4 and IL-10 mRNA accumulation upon infection with both strains of T. cruzi. A T_h2-like' response (higher IL-4 and IL-10 mRNA to IFN-γ mRNA ratio), was also observed when cells from non-infected CD8 - mice were stimulated with T cell mitogens.     

Acute exercise causes an enhancement of tissue renin-angiotensin system in the kidney in rats

AIMS: Initially, the renin-angiotensin system (RAS) produced through the classical endocrine pathway was well known for its regulation of blood pressure. However, it was revealed that a local autocrine and/or paracrine RAS may exist in a number of tissues (such as kidney). Exercise causes a redistribution of tissue blood flow, by which the blood flow is greatly increased in active muscles, whereas it is decreased in the splanchnic circulation (such as in the kidney). We hypothesized that exercise causes an enhancement of tissue RAS in the kidney. METHODS: We studied whether exercise affects expression of angiotensinogen and angiotensin-converting enzyme (ACE) and tissue angiotensin II level in the kidney. The rats performed treadmill running for 30-min. Immediately after this exercise, kidney was quickly removed. Control rats remained at rest during this 30-min period. RESULTS: The expression of angiotensinogen mRNA in the kidney was markedly higher in the exercise rats than in the control rats. ACE mRNA in the kidney was significantly higher in the exercise rats than in the control rats. Western blot analysis confirmed significant upregulation of ACE protein in the kidney after exercise. Tissue angiotensin II level was also increased by exercise. CONCLUSION: The present study suggests that the exercise-induced enhancement of tissue RAS in the kidney causes vasoconstriction and hence decreases blood flow in the kidney, which are helpful in increasing blood flow in active muscles, thereby contributing to the redistribution of blood flow during exercise.     

Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans

We investigated the functional roles of circulating and locally produced angiotensin II (Ang II) in fasting and postprandial adipose tissue blood flow (ATBF) regulation and examined the interaction between Ang II and nitric oxide (NO) in ATBF regulation. Local effects of the pharmacological agents (or contralateral saline) on ATBF, measured with ¹³³Xe wash-out, were assessed using the recently developed microinfusion technique. Fasting and postprandial (75 g glucose challenge) ATBF regulation was investigated in nine lean healthy subjects (age, 29 ± 3 years; BMI, 23.4 ± 0.7 kg m⁻²) using local Ang II stimulation, Ang II type 1 (AT₁) receptor blockade, and angiotensin-converting enzyme (ACE) inhibition. Furthermore, NO synthase (NOS) blockade alone and in combination with AT₁ receptor blockade was used to examine the interaction between Ang II and NO. Ang II induced a dose-dependent decrease in ATBF (10⁻⁹ m : −16%, P = 0.04; 10⁻⁷ m : −33%, P < 0.01; 10⁻⁵ m : −53% P < 0.01). Fasting ATBF was not affected by ACE inhibition, but was increased by ∼55% ( P < 0.01) by AT₁ receptor blockade. NOS blockade induced a ∼30% ( P = 0.001) decrease in fasting ATBF. Combined AT₁ receptor and NOS blockade increased ATBF by ∼40% ( P = 0.003). ACE inhibition and AT₁ receptor blockade did not affect the postprandial increase in ATBF. We therefore conclude that circulating Ang II is a major regulator of fasting ATBF, and a major proportion of the Ang II-induced decrease in ATBF is NO independent. Locally produced Ang II does not appear to regulate ATBF. Ang II appears to have no major effect on the postprandial enhancement of ATBF.     

白细胞介素18受体在人类外周血单个核细胞及肾组织表达的研究

目的 :进一步明确白细胞介素 (IL 18)在肾组织免疫性损伤中的作用。方法 :应用半定量逆转录 多聚酶链反应(RT PCR)技术检测 16例正常人 ,16例原发性系膜增生性肾小球肾炎 (MsPGN)患者以及 18例狼疮性肾炎 (LN)患者外周血单个核细胞 (PBMC)白细胞介素 18受体 (IL 18R)α链mRNA的表达量 ,并用免疫组化方法检测 6例正常肾组织 ,16例MsPGN)患者及 18例LN患者肾组织IL 18Rα链蛋白表达量。结果 :MsPGN患者PBMCIL 18RmRNA表达量较正常组有所增高 ,但未达统计学意义 (P >0 0 5 ) ,LN患者PBMCIL 18RmRNA表达量较正常人显著增高 (P <0 0 0 1) ;正常肾组织存在较弱的IL 18R表达 ,MsPGN患者肾组织IL 18R表达量较正常肾组织有所增强 ,但未达统计学差异 ,而LN患者肾组织IL 18R的表达量较正常肾组及MsPGN组均显著增强 (P <0 0 0 1) ,但Pearson相关分析发现LN患者PBMC及肾组织IL 18R表达量均不与血清肌酐 (Scr)水平及 2 4小时尿蛋白排泌量 (2 4h UPE)存在相关关系。结论 :IL 18信号在全身系统及肾组织局部的免疫调节中起一定的作用 ;IL 18在肾功能未严重损害MsPGN患者的发病过程中可能所起作用不大 ;LN患者不但存在IL 18的过量产生 ,而且存在着IL 18过度作用的问题 ,抑制过强的IL 18作用信号可能是LN治疗的新途径。