Renin-angiotensin system in the kidney: What is new?

The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin II(Ang II) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang IIformation or even active Ang II-derived peptides have now been described acting on Ang II AT₁ or AT₂ receptors, or in receptors which have recently been cloned, such as Mas and AT₄. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang II formation. This in situ formation, especially in the kidney, increases Ang II levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang II effects, improves the development of new drugs for treating hypertension and cardiovascular diseases.     

The renin-angiotensin system in cutaneous hypertrophic scar and keloid formation

Hypertrophic scar and keloid are two types of fibroproliferative conditions that result from excessive extracellular matrix production. The underlying pathological mechanism is not entirely clear. Activation of the renin-angiotensin system (RAS) is associated with fibrosis in various organs. RAS components including angiotensin II (Ang II), angiotensin AT₁ and AT₂ receptors, and angiotensin-converting enzyme (ACE) are expressed in the skin and act independently from the plasma RAS. AT₁ receptors, which are usually the dominating receptor subtype, promote fibrosis and scar formation, while AT₂ receptors inhibit the aforementioned AT₁ receptor-coupled effects. Elevated angiotensin II (Ang II) levels acting on the AT₁ receptor contribute to skin scar formation through increased expression of inflammatory factors such as interleukin-6 (IL-6), angiogenic factors such as vascular endothelial growth factor (VEGF) and fibrinogenic factors such as transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF), while at the same time suppressing the anti-fibrotic tissue inhibitors of matrix metalloproteinase (TIMPs). First, small clinical trials have provided evidence that inhibition of the ACE/Ang II/ AT₁ receptor axis may be effective in the treatment of hypertrophic scars/keloids. This review provides a detailed overview of the current literature on the RAS in skin, wound healing and scar formation and discusses the translational potential of targeting this hormonal system for treatment and prevention of hypertrophic scars and keloids.     

寻常型银屑病皮损中血管紧张素Ⅱ及血管紧张素转化酶的检测

目的:检测寻常型银屑病皮损中血管紧张素Ⅱ(AngⅡ)及血管紧张素转化酶(ACE)的水平变化。方法:应用荧光定量聚合酶链反应(FQ-PCR)和免疫组化技术检测30例寻常型银屑病患者(进行期17例,静止期13例)皮损AngⅡ和ACE mRNA及蛋白质的表达。结果:银屑病患者皮损中AngⅡ和ACE mRNA及蛋白质的表达明显高于正常人对照组(P0.001),且进行期高于静止期(P0.001)。结论:AngⅡ和ACE在银屑病皮损中表达上调,推测可能与银屑病皮损中新血管的形成有关。     

Human skin: source of and target organ for angiotensin II

The present study examined the expression of angiotensin receptors in human skin, the potential synthesis of angiotensin II (Ang II) in this location and looked for a first insight into physiological functions. AT1 and AT2 receptors were found within the epidermis and in dermal vessel walls. The same expression pattern was found for angiotensinogen, renin and angiotensin-converting enzyme (ACE). All components could additionally be demonstrated at mRNA level in cultured primary keratinocytes, melanocytes, dermal fibroblasts and dermal microvascular endothelial cells, except for AT2 receptors in melanocytes. The ability of cutaneous cells to synthesize Ang II was proved by identifying the molecule in cultured keratinocytes. Furthermore, in artificially wounded keratinocyte monolayers, ACE-mRNA expression was rapidly increased, and enhanced ACE expression was still found in cutaneous human scars 3 months after wounding. These findings suggest that the complete renin-angiotensin system is present in human skin and plays a role in normal cutaneous homeostasis as well as in human cutaneous wound healing.     

High association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS) is a common ulcerative disease of the oral mucosa. Oral ulcers are also the most common feature of Behçet’s disease (BD). Association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with BD has been reported in Turkish population. The aim of the present study was to investigate the possible association between ACE gene I/D polymorphism and RAS, and evaluate if there was an association with clinical features in a relatively large cohort of Turkish patients. The study included 198 patients affected by RAS and 214 healthy controls. ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction with I and D allele-specific primers. The genotype and allele frequencies of I/D polymorphism showed statistically significant differences between RAS patients and controls (p < 0.0001 and p < 0.0001, respectively). After stratifying RAS patients according to clinical and demographical characteristics, no significant association was observed. In conclusion, the results of this study suggest that I/D polymorphism of the ACE gene was positively associated with predisposition to develop RAS in Turkish population. Further studies with larger populations are recommended.     

Association between the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and risk for psoriasis in a Chinese population in Taiwan

BACKGROUND: Genetic factors play an important role in susceptibility for psoriasis. The angiotensin I-converting enzyme (ACE) is expressed by keratinocytes. Administration of ACE inhibitors may induce or exacerbate psoriasis in clinical practice. Thus, ACE gene variants may contribute to the genetic background of psoriasis. OBJECTIVES: To assess the role of the ACE insertion/deletion (I/D) polymorphism in psoriasis among ethnically Chinese Taiwanese subjects. METHODS: In total, 312 patients with psoriasis and 615 control subjects were analysed for the ACE I/D polymorphism by polymerase chain reaction. RESULTS: A marginally significant difference (P=0 x 035) was found in the distribution of ACE I/D genotype frequencies between patients with psoriasis and controls. The frequency of the II genotype in patients with psoriasis was significantly higher than that in the control group (55 x 1% vs. 46 x 7%, respectively, P=0 x 015). Although the I allele frequency in patients with psoriasis (72 x 4%) was higher than that in the control group (68 x 2%), the difference was not significantly different (P=0 x 062). After adjusting for age and gender, carriers of the II genotype were 1 x 45 (95% confidence interval 1 x 09-1 x 92) times more likely than noncarriers to have psoriasis (P=0 x 010). CONCLUSIONS: Our results suggest that the presence of the I allele may confer susceptibility to development of psoriasis among ethnically Chinese Taiwanese individuals.     

Angiotensin II enhances EGF receptor expression levels via ROS formation in HaCaT cells

BACKGROUND: Recent work has shown a novel function of angiotensin II (Ang II) in skin wound healing in which reactive oxygen species might be involved. As Ang II is known to increase superoxide production by activating NADPH oxidase in some non-phagocytic cells, we hypothesized that the produced superoxide by NADPH activation could contribute to the regulation of epidermal growth factor receptor (EGFR) in keratinocytes. OBJECTIVE: We examined whether Ang II could generate superoxide and enhance EGFR expression levels in HaCaT cells. METHODS: Superoxide formation was assessed by using hydroethidine. EGFR expression levels were examined by Western blotting. RESULTS: Ang II (1-100 microM) increased the superoxide formation. Ang II (1-100 microM) resulted in a dose-dependent increase in cell proliferation in HaCaT cells. Heparin-binding epidermal growth factor activated the EGFR at 5-10 min. Although Ang II did not activate the EGFR, the expression levels of EGFR protein were increased in HaCaT cells treated with Ang II (1 microM) at 6h. Apocynin, a NADPH oxidase inhibitor, decreased the expression levels of EGFR. Xanthine/xanthine oxidase system, an exogenous superoxide generating system, enhanced the EGFR protein expression. Although Ang II did not affect the nitric oxide (NO) production, a NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester suppressed the Ang II-induced EGFR expression levels in HaCaT cells. Thus, constitutive NO is required for the Ang II-induced EGFR expression in HaCaT cells. CONCLUSION: These results suggest that Ang II enhances the cell proliferation and EGFR expression via superoxide production under the regulation of NO in HaCaT cells, implying that Ang II may regulate the proliferation, differentiation and tumorigenesis of the epidermis by harmonizing the superoxide and NO production.     

ACE基因插入/缺失多态性与银屑病关系的研究

目的探讨血管紧张素转换酶(ACE)基因插入/缺失多态性与中国人群银屑病之间的关系。方法应用聚合酶链反应(PCR)对泰安地区88例银屑病患者及95例正常对照者的ACE基因插入/缺失多态性进行检测和分析。结果银屑病患者与正常对照者的II,ID,DD基因型及等位基因分布频率均无显著性差异(P>0.05),进一步分析显示ACE插入/缺失基因多态性与银屑病患者的性别及有无明确的家族史均无关联。结论ACE基因插入/缺失多态性可能不是中国人群银屑病发病的遗传学危险因素。     

Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: protective and predisposing effects of genotypes in disease susceptibility and progression

Vitiligo is a depigmenting skin disorder with profound heterogenity in its aetio-pathophysiology, and is associated with inter-individual variation in progression of disease. Angiotensin converting enzyme (ACE) is a regulator of renin angiotensin system (RAS) that plays an important role in the physiology of the vasculature, blood pressure, inflammation, adipocyte distribution of various diseases. The present study was carried out in 243 vitiligo patients (132 males and 111 females), aged between 3-62 years with a mean age at onset of 21.6 ± 13.6 yrs, and in 205 healthy controls of south Indian origin. The main objectives of the present study were to evaluate the ACE I/D (insertion/deletion) polymorphism in the patient and control groups. Further, I/D genotypes were compared among the patients with and without the family history of vitiligo as well as the progression of the disease, through polymerase chain reaction (PCR) methods.

The results revealed a highly significant association of DD genotype with disease susceptibility (p?相似文献   

Association of insertion/deletion polymorphism of the angiotensin-converting enzyme gene with angio-oedema accompanying chronic urticaria but not chronic urticaria without angio-oedema or the autologous serum skin test response

Background Chronic urticaria is defined as the daily or almost daily occurrence of weals for more than 6 weeks. The underlying pathophysiology is reported to be mast cell activation, with release of mast cell mediators, predominantly histamine. Substance P is a neuropeptide and has the capacity to provoke histamine release from skin mast cells. Angiotensin‐converting enzyme (ACE), widely expressed in skin, is one of the major peptidase for the degradation of substance P. An insertion/deletion polymorphism (I/D) in the ACE gene has been reported to be related to the levels of enzyme. Objective An increase in substance P levels due to a polymorphism in ACE gene might be related to the pathology. Thus, we aimed to investigate whether there is an association between ACE I/D polymorphism and chronic ordinary urticaria. Methods Ninety‐five patients with chronic ordinary urticaria were recruited and divided into two groups according to autologous serum skin test status and accompanying angio‐oedema. One hundred and sixty‐one healthy subjects were enrolled as control group. All participants were genotyped for I/D polymorphism in intron 16 of the ACE gene by polymerase chain reaction. Results A statistically significant association was not found between ACE I/D polymorphism and chronic ordinary urticaria. Further analyses of chronic ordinary urticaria patients showed that ACE I/D polymorphism was not associated with autologous serum skin test status of patients. However, the frequencies of II genotype and I allele were statistically significantly higher in chronic ordinary urticaria patients with accompanying angio‐oedema with regard to angio‐oedema‐negative patients (II genotype: 24% vs. 9%, P = 0.0002; I allele: 58% vs. 27%, P = 0.0001) and control group (II genotype: 24% vs. 19%, P = 0.01; I allele: 58% vs. 41%, P = 0.03). Conclusion The results of this study suggest no evidence of an association between ACE I/D polymorphism and risk of developing chronic ordinary urticaria. However, it can be a contributing factor to susceptibility of angio‐oedema in chronic ordinary urticaria.     

COMP-angiopoietin 1 Gene Transfer Enhances Cutaneous Wound Healing by Promoting Angiogenesis

Background

Angiogenesis is crucial for wound healing and exogenous supplements of the angiogenic growth factors have been known to promote cutaneous wound healing. Angiopoietin (Ang) 1 is a recently discovered angiogenic factor and there have been few studies of its effect on cutaneous wound healing.

Objective

We examined the effect of Ang 1 on cutaneous wound healing.

Methods

Cartilage oligomeric matrix protein (COMP)-Ang 1 (Ade-COMP-Ang 1)- was intravenously injected to rats two days before surgery creating full-thickness wounds. The clinical wound healing rate and the number of vessels in the skin samples were evaluated on days 3, 7 and 14 post operation.

Results

At post-operation day 3, 7 and 14, the clinical wound healing rate was 38.3%, 59.4% and 92.1%, respectively, in the Ade-COMP-Ang 1-treated group, compared with 20.5%, 47.5% and 87.3%, respectively, in the Ade-LacZ-treated group. There were significant differences in the results of day 3 and day 7 between two groups (p<0.05). Histopathologically, the number of the vessels of the Ade-COMP-Ang 1-treated group was 73.7, 94.1 and 62.7 at day 3, 7 and 14, compared with that of the Ade-LacZ-treated group, 53.5, 83.9, and 56.9. The differences in the results of the two groups were statistically significant (p<0.05).

Conclusion

These results indicate that Ade-COMP-Ang 1 therapy significantly accelerats wound healing by promoting angiogenesis. However, further study using Ade-COMP-Ang 1 gene therapy for chronic wounds in which the formation of new blood vessels is impaired is needed in the near future.     

Localization of angiotensin converting enzyme (ACE) in granulomas of sarcoidosis cutaneous lesions

Using an immunofluorescent technique, the localization of angiotensin converting enzyme (ACE) was investigated in granuloma lesions from the skin of three sarcoidosis cases. Specific fluorescence was observed in epithelioid cells in the sarcoidosis granulomas examined. However, it was not found in any other granulomatous diseases observed as controls, which included granuloma annulare, foreign body granuloma and lupus miliaris disseminatus faciei. These results indicate that ACE is specifically localized in the epithelioid cells in cutaneous granuloma lesions of sarcoidosis; in one case, it was also observed in Langhans giant cells. Therefore, it is suggested that examination for ACE in cutaneous lesions using an immunofluorescent technique is very useful for the diagnosis of sarcoidosis in the skin. We suggest that epithelioid cells of granulomas in sarcoidosis cutaneous lesions may play an important role in the increase of serum ACE activity.     

Association of insertion/deletion polymorphism of the angiotensin-converting enzyme gene with psoriasis

BACKGROUND: Genetic factors are likely to be of fundamental importance in the pathogenesis of psoriasis. There are reports concerning the induction or/and exacerbation of psoriasis by angiotensin-converting enzyme (ACE) inhibitors, which have been attributed to the ACE inhibitor-induced augmentation of kinin levels in skin. However, to the best of our knowledge there has been no molecular genetic study investigating whether ACE insertion/deletion (I/D) polymorphism may contribute to the genetic background in psoriasis. OBJECTIVES: To assess the role of ACE I/D polymorphism in psoriasis. METHODS: A group of 86 patients with psoriasis and 154 control subjects were analysed for ACE I/D polymorphism by polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in psoriatic patients was not significantly different from controls. Further analyses of psoriasis patients showed that ACE I/D polymorphism was not associated with age at onset of disease, clinical type of psoriasis or gender. However, the frequency of the I allele was significantly higher in patients with a positive family history of psoriasis than in those with no family history (sporadic psoriasis) (48% vs. 32%; P =0.03). In addition, the I allele was found significantly more frequently in type I psoriasis patients (onset < 40 years and positive family history) than in type II psoriasis patients (onset >/= 40 years, no family history) (48% vs. 27%; P = 0.04). CONCLUSIONS: Our results suggest that the presence of the I allele may confer susceptibility to development of psoriasis in individuals from psoriatic families.     

The angiotensin-converting enzyme insertion/deletion and the endothelin -134 3A/4A gene polymorphisms in patients with chronic plaque psoriasis

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. Vasoactive peptides such as endothelin-1 (ET-1) and bradykinin have previously been implicated in the pathogenesis of chronic plaque psoriasis. The angiotensin-converting enzyme (ACE) gene carries a 287-base pair insertion/deletion (I/D) gene polymorphism, which is associated with plasma concentrations of bradykinin-degrading ACE. A functional polymorphism (EDN1 -134 3A/4A) in the gene encoding ET-1 has been shown to affect ET-1 expression. The purpose of the present study was thus to investigate a hypothesized association between these gene polymorphisms and the presence of chronic plaque psoriasis. METHODS: The present case-control study comprised 207 patients with chronic plaque psoriasis (136 with early onset and 71 with late onset disease) and 182 control subjects. Genotypes of EDN1 and ACE were determined by a 5' exonuclease assay (Taqman). RESULTS: The prevalence of the homozygous ACE II genotype was significantly higher in patients with early-onset psoriasis than among control subjects (30.9% vs 19.2%, P = 0.016), yielding an odds ratio of 1.88 [95% confidence interval (CI): 1.12-3.15] for early-onset disease. For late-onset psoriasis, presence of the ACE II genotype was associated with a non-significant odds ratio 1.54 (95% CI: 0.81-2.92). As for the EDN1 -134 3A/4A gene polymorphism, no significant differences in genotype distributions were found between patients with either early- or late-onset psoriasis and control subjects (EDN1 -134 4A/4A: 9.6% in early-onset and 5.6% late-onset psoriasis vs 7.7% in controls; P > 0.05). CONCLUSIONS: Our data suggest that homozygosity for the ACE I allele may affect susceptibility to early-onset psoriasis.     

Characterization of angiotensin-converting enzyme expression during epidermis morphogenesis in humans: a potential marker for epidermal stem cells

Background  Recent evidence has revealed that angiotensin-converting enzyme (ACE) participates in cutaneous wound healing and contributes to the pathophysiological process of some skin diseases. However, little is known about the role of ACE in epidermis morphogenesis during development.
Objective  To clarify the expression pattern of ACE during embryonic development of human skin.
Methods  Skin samples were obtained from aborted fetuses at different gestational ages and from healthy individuals. Localization of ACE, together with β₁-integrin, keratin 19 (K19) and p63 was examined by immunofluorescence and immunohistochemical staining.
Results  In human fetal skin, at 11–13 weeks of gestation, ACE-positive cells were observed in the primitive epidermis. As the fetuses developed, ACE-positive cells appeared in all the epidermal layers. From 21 weeks of gestation, ACE expression was largely restricted to the basal layer of the fetal epidermis. In contrast, ACE-positive cells were found only in the adult skin basal layer which harbours epidermal stem cells. To explore the possible link between ACE and epidermal stem cells, we further examined the expression of β₁-integrin, K19 and p63, the putative markers for epidermal stem cells. Consistent with the results of ACE expression, from 21 weeks of gestation, the expression of β₁-integrin, K19 and p63 was mainly confined to the basal layer. Immunofluorescent double labelling revealed that ACE-positive cells substantially overlapped with β₁-integrin-, K19- and p63-positive cells.
Conclusions  Our results suggest that ACE may play a role in human epidermis morphogenesis during fetal life and serve as an unrecognized marker for keratinocyte progenitor cells.     

Monitoring neuropeptide-specific proteases: processing of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone in the skin

The neuroendocrine precursor protein proopiomelanocortin (POMC) and its derived neuropeptides are involved in a number of important regulatory processes in the central nervous system as well as in peripheral tissues. Despite its important role in controlling the local activation of melanocortin (MC) receptors, the extracellular proteolytic processing of POMC peptides has received little attention. The mechanisms relevant for controlling the bioavailability of adrenocorticotropin and melanocyte-stimulating hormones for the corresponding MC receptors in the skin by specific peptidases such as neprilysin (neutral endopeptidase; NEP) or angiotensin-converting enzyme (ACE) have been addressed in a number of recent investigations. This review summarizes the current body of knowledge concerning the qualitative and quantitative POMC peptide processing with respect to the action and specificity of NEP and ACE and discusses relevant recent analytical methodologies.     

Regulatory roles of nitric oxide and angiotensin II on renal tubular transport

Renal tubules regulate blood pressure and humoral homeostasis. Mediators that play a significant role in regulating the transport of solutes and water include angiotensin II (AngII) and nitric oxide (NO). AngIIcan significantly raise blood pressure via effects on the heart, vasculature, and renal tubules. AngII generally stimulates sodium reabsorption by triggering sodium and fluid retention in almost all segments of renal tubules. Stimulation of renal proximal tubule (PT) transport is thought to be essential for AngII-mediated hypertension. However, AngII has a biphasic effect on in vitro PT transport in mice, rats, and rabbits: stimulation at low concentrations and inhibition at high concentrations. On the other hand, NO is generally thought to inhibit renal tubular transport. In PTs, NO seems to be involved in the inhibitory effect of AngII. A recent study reports a surprising finding: AngII has a monophasic stimulatory effect on human PT transport. Detailed analysis of signalling mechanisms indicates that in contrast to other species, the human NO/guanosine 3’,5’-cyclic monophosphate/extracellular signal-regulated kinase pathway seems to mediate this effect of Ang II on PT transport. In this review we will discuss recent progress in understanding the effects of AngII and NO on renal tubular transport.