Receptor de la enzima convertidora de angiotensina y su correlación con COVID-19 ¿Qué conocemos hasta el momento? / Angiotensin Converting Enzime Receptor and COVID-19 Correlation ¿What do we know so far?

Resumen Introducción: el SARS-COV-2 es un nuevo virus que ha traído nuevos retos a los sistemas de salud a nivel mundial y que ha generado controversia en la continuidad en el uso de bloqueadores del receptor de angiotensina por su correlación fisiopatológica con el SARS-COV-2. Objetivo: presentar la evidencia disponible y las actuales recomendaciones sobre el uso de receptores de la enzima convertidora de angiotensina en el tratamiento para COVID-19. Materiales y métodos: se realizó una búsqueda narrativa en la base de datos PubMed sobre artículos que hablaran acerca del receptor de la enzima convertidora de angiotensina asociado a la pandemia actual por COVID-19. El límite de publicación fue el 13 de abril de 2020 y se incluyeron artículos en todos los idiomas. Resultados: se encontraron 14 artículos con contenido científico significativo para el objetivo de la presente revisión. Conclusión: la fisiopatología del SARS-COV-2 aún es desconocida, así como la efectividad de diferentes fármacos de uso cotidiano para su tratamiento. Dentro de los diferentes medicamentos que se han probado para detener el contagio y sus efectos están aquellos con efecto sobre el receptor de la enzima convertidora de angiotensina.

Abstract Introduction: As a new disease, SARS-COV-2 is a new challenge for healthcare system worldwide, with physiopathology under study and controversy about Angiotensin Converting Enzyme Blockers use because of It's physiopatological correlation with SARS-Cov-2. Objetive: Search for novel literature and recent recomendations about use of Angiotensin Converting Enzyme Blockers during Covid-19 illness. Materials and Methods: We look for narrative literature at PubMed Database for articles about Angiotensin Converting Enzyme and Covid-19 pandemic. Searching limit was April 13 of2.020, we included all languages. Results. We included 14 articles with significative scientific content for review objetive. Conclusion: SARS-Cov-2 Physiopatology is still unclear, also, pharmacology effectiveness in it's treatment. One of these pharmacology groups are the Angiotensin Converting Enzyme Blockers with uncertainty about it's safety during COVID-19 illness.

Tratamiento de la hipertensión arterial en presencia de enfermedad renal crónica / Treatment of hypertension in CKD patient

La mejoría en la sobrevida también ofrece una mayor posibilidad de padecer enfermedades crónicas degenerativas entre las que destacan la diabetes mellitus y la hipertensión arterial (HTA). La enfermedad renal crónica (ERC) actualmente constituye una pandemia y la HTA está presente en prácticamente todos los estadios de la ERC, el descontrol hipertensivo y la necesidad de ingerir más fármacos para obtener valores tensionales adecuados se hace más evidente a medida que progresa el estadio de la enfermedad. El enfermo renal presenta HTA de difícil control, en él se conjugan la activación adrenérgica, activación del sistema nervioso renina angiotensina aldosterona, la retención hídrica y mecanismos vasculares. El tratamiento antihipertensivo vigente en presencia de daño renal se enfoca a disminuir las cifras de presión arterial, disminuir el riesgo cardiovascular y brindar renoprotección, los antagonistas de receptores de angiotensina han demostrado ser la terapia farmacológica de elección independientemente de la enfermedad subyacente y del grado de proteinuria, la combinación con IECA no resulta en un mayor beneficio y si en efectos adversos graves como hipercalemia, inclusive potencialmente letales que incluyen síndrome de muerte súbita. El tratamiento de la HTA en la ERC deberá ir más allá de sólo la reducción de cifras de presión arterial, al considerar que en estos pacientes el riesgo cardiovascular se encuentra muy incrementado y el enlentecimiento de la progresión del daño renal es imperativo.

Improvement in survival involves a greater possibility of developing chronic degenerative diseases among which diabetes mellitus and hypertension stand out. Chronic kidney disease (CKD) is now a pandemic and hypertension is present in virtually all stages of CKD, the uncontrolled hypertension and the need to ingest more drugs to have adequate blood pressure values becomes more evident as disease stage progresses. Renal patients have high blood pressure difficult to control, and combine adrenergic activation, activation of the renin angiotensin aldosterone nervous system, water retention and vascular mechanisms. Current antihyperten-sive treatment when kidney damage is present focuses on reducing blood pressure, reducing cardiovascular risk and providing renoprotection; angiotensin receptor antagonists have been proven to be the pharmacological therapy of choice regardless of the underlying disease and the degree of proteinuria, the combination with ACEI does not result in a greater benefit but do produce serious adverse effects such as hyperkalemia, and even potentially lethal damage, including sudden death syndrome. Treatment of hypertension in CKD must go beyond just reducing blood pressure, considering that cardiovascular risk is greatly increased in these patients and that slowing the progression of kidney damage is imperative.

Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT1 receptor (AT1-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO2 = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT1-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT1-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT1-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT1-R staining, but C animals showed weak iNOS and AT1-R staining. Macrophages of L and P animals showed moderate and weak AT2-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT1-R blockade. We suggest that AT1-R blockade might act through AT2-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

Effect of conversion from CCB to ARB in treatment of hypertension and proteinuria in kidney transplant recipients / 中华器官移植杂志

Objective To compare the efficacy and safety of conversion from CCB to ARB in the treatment of hypertension and proteinuria in kidney transplant recipients.Methods 127 long-term recipients who used CCB as their anti-hypertensive drug were enrolled.All recipients had stable renal function and no diabetes.Recipients were randomly assigned to experimental group (65 cases) which received ARB (Losartan,50～ 100 mg/day) instead of CCB,or control group (62 cases) which received routine CCB.All recipients were followed up for 2 years.Blood count,urinalysis,liver and kidney chemistry,blood lipid,serum electrolytes,24-h urine protein,blood concentration of CNI drugs and other biochemical indexes were observed.Results During the 2-year follow-up,the blood pressure of the two groups was maintained within normal level.The 24-h urine protein was decreased in the experimental group ( 176.32 ± 54.54 to 155.69 ± 62.25,P＜0.05),but increased slightly in the control group (P＞0.05).Although the blood lipid of the experimental group was not different before and after the follow-up,the high density lipoprotein (HDL) was increased statistically (2.25 ± 0.26 to 2.46 ±0.31,P＜0.05).The blood count,liver and kidney chemistry,serum potassium,blood concentration of CNI drugs in both groups showed no significant differences.Conclusion Both CCB and ARB could be effectively and safely used for the treatment of hypertension and proteinuria in kidney transplant recipients.ARB would be more effective in reducing cardiovascular disease (CVD)rate and decreasing proteinuria.

Maternal undernutrition and the offspring kidney: from fetal to adult life

Maternal dietary protein restriction during pregnancy is associated with low fetal birth weight and leads to renal morphological and physiological changes. Different mechanisms can contribute to this phenotype: exposure to fetal glucocorticoid, alterations in the components of the renin-angiotensin system, apoptosis, and DNA methylation. A low-protein diet during gestation decreases the activity of placental 11ß-hydroxysteroid dehydrogenase, exposing the fetus to glucocorticoids and resetting the hypothalamic-pituitary-adrenal axis in the offspring. The abnormal function/expression of type 1 (AT1R) or type 2 (AT2R) AngII receptors during any period of life may be the consequence or cause of renal adaptation. AT1R is up-regulated, compared with control, on the first day after birth of offspring born to low-protein diet mothers, but this protein appears to be down-regulated by 12 days of age and thereafter. In these offspring, AT2R expression differs from control at 1 day of age, but is also down-regulated thereafter, with low nephron numbers at all ages: from the fetal period, at the end of nephron formation, and during adulthood. However, during adulthood, the glomerular filtration rate is not altered, due to glomerulus and podocyte hypertrophy. Kidney tubule transporters are regulated by physiological mechanisms; Na+/K+-ATPase is inhibited by AngII and, in this model, the down-regulated AngII receptors fail to inhibit Na+/K+-ATPase, leading to increased Na+ reabsorption, contributing to the hypertensive status. We also considered the modulation of pro-apoptotic and anti-apoptotic factors during nephrogenesis, since organogenesis depends upon a tight balance between proliferation, differentiation and cell death.

Expression of angiotensin II and its receptors in a rat model of chronic cyclosporine nephrotoxicity / 第二军医大学学报

Objective: To observe the expression of angiotensin II ( Ang II) and its receptors in a rat model of chronic cyclosporine (CsA) nephrotoxicity. Methods: Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administering CsA (15 mg/kg s. c.) for 4 weeks. The body weight, systolic blood pressure, serum CsA, serum creatinine (Cr), and creatinine clearance rate (Ccr) of rats were examined in each group. Trichrome staining was used to observe the tubulointerstitial fibrosis; expressions of Ang II and its receptors (AT1 and AT2) were examined by immunohistochemical staining and Western blotting analysis. Results: Compared with the control rats, CsA-treated rats showed decreased body weight, increased Cr, decreased Ccr and tubulointerstitial fibrosis (P < 0.01). Immunohistochemistry revealed that the immunoreactivity of Ang II was significantly increased in the CsA-treated rats (47±7 vs 13±4, P < 0.01), with the immunoreactivity mainly locating to the juxtaglomerular afferent arterioles, and the immunoreactivity was significantly correlated with tubulointerstitial fibrosis (r=0. 769, P<0.001). Western blotting analysis showed significantly decreased AT1 expression ([114±14]% vs [42±6]%, P<0.01) and increased AT2 expression ([129±23]% vs [469±43]%, P<0.01). Conclusion: The findings of our study suggest that the intrarenal renin-angiotensin system is activated during chronic CsA nephrotoxicity, which is manifested by increased Ang II immunoreactivity, and this increased immunoreactivity is closely related to tubulointerstitial fibrosis.

Expression of peroxisome proliferator-activated receptor-γ and angioteusin Ⅱ receptor protein in chronic pancreatitis tissue / 中华胰腺病杂志

Objective To investigate the expression of peroxisome proliferator-activated receptor-γ(PPAR-γ) and angiotensin receptor (AT2R) in chronic pancreatitis tissue. Methods Between April 2006 and February 2009, 24 patients were pathologically diagnosed as chronic pancreatitis were enrolled and 12 samples of normal pancreatic tissues were treated as controls. Immunohistochemical staining was used to detect PPAR-γ and AT1R, AT2R expression in pancreatic tissues. Results PPAR-γ and AT1R were mostly negatively expressed in normal pancreatic tissues, the positive scores were 0.33±0.49 and 0.42 ± 0. 51, respectively, while AT2R were weakly positively or negatively expressed in acinus and islet cell, and it was weakly positively expressed in ductal epithelial cells, the positive score was 2. 33 ± 1. 37. In chronic pancreatitis tissue, PPAR-γ, AT1R and AT2R were positively expressed in acinus, ductal epithelial cells, and islet cell, the positive scores were 3.28 ± 2.46, 4.36 ± 2.80 and 4.61 ± 2.89, which were significantly higher than those in the normal group (P<0.01, P <0.01, P<0.05). Conclusions PPAR-γ, AT1R and AT2R were positively expressed in chronic pancreatitis tissue, and they may be the treatment target of chronic pancreatitis.

Effect of RAS on islets β-cell function and the role and the mechanism in which AT1R involves / 中华内分泌代谢杂志

Objective To study the role of pancreatic renin-angiotensin system (RAS) on insulin secretion, proliferation, apoptosis, oxidative stress, and fibrosis of β-cells. Methods The effect of angiotensin Ⅱ on βTC3 cells was studied and the role and mechanism of AT1 R were analyzed with RNAi technology. The expression of AT1 R was measured by Western Blotting. The change of intracellular calcium was detected by microfluorimetry with Furo3-1oaded cells. Peroxide-sensitive fluorescent probe DCFH-DA was used to analyze intracellular ROS by flow cytometry. Real-time PCR was performed to evaluate mRNA levels related to proliferation and fibrosis in βTC3 cells. Apoptosis was detected by flow cytometry and Tunel method. Results Insulin secretion was significantly increased up to four fold and the level of intracellular calcium was sharply increased in response to high glucose in βTC3 cells. Angiotensin Ⅱ has no direct effect on insulin secretion in βTC3 cells and its role in secretion was associated with the role in proliferation. Oxidative stress in βTC3 cells caused by angiotensin Ⅱ may be partially mediated through AT1R, protein kinase C and NAD(P) H. With the decrease of AT1R expression by RNAi technology, apoptosis, and fibrosis of βTC3 cells induced by angiotensin Ⅱ might be ameliorated.Conclusions By means of AT1R, angiotensin Ⅱ plays an important role in insulin secretion, proliferation,apoptosis, oxidative stress and fibrosis in β-cells.