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ABSTRACT Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.
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Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla (RVLM) have been implicated in stress-induced hypertension (SIH). Prorenin, a member of the brain renin-angiotensin system (RAS), can directly activate microglia. The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats. Rats were subjected to intermittent electric foot-shocks plus noise, this stress was administered for 2 h twice daily for 15 consecutive days, and mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were monitored. The results showed that MAP and RSNA were augmented, and this paralleled increased pro-inflammatory phenotype (M1) switching. Prorenin and its receptor (PRR) expression and the NLR family pyrin domain containing 3 (NLRP3) activation were increased in RVLM of SIH rats. In addition, PLX5622 (a microglial depletion agent), MCC950 (a NLRP3 inhibitor), and/or PRO20 (a (Pro)renin receptor antagonist) had antihypertensive effects in the rats. The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622. Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in prorenin-stimulated microglia. Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation, while MCC950 decreased the M1 polarization. In conclusion, upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH, mediated by activation of the microglia-derived NLRP3 inflammasome. The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.
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(Pro)renin receptor(PRR)was organically identified as a specific receptor for prorenin and renin to regulate the activity of renin-angiotensin system(RAS). Increasing evidence suggests that PRR plays a multitude functions in a RAS-dependent and independent manner. The extracellular domain of PRR is cleaved by furin or ADAM19 to produce a 28-ku soluble PRR(sPRR) while the intracellular domain,M8.9,is a subunit of vacuolar H+-ATPase that mediates H+transport. PRR is critically involved in embryogenesis in low vertebrates and mammals. In recent years ,a significant progress has been made in identifying the physiological and pathophysiological functions of renal PRR. PRR has been identified as an important regulator of urine concentrating capability mostly due to its ability to upregulate to aquaporin-2(AQP2)in the collecting duct and Na+,K+,2Cl-cotransporter(NKCC2)in the thick ascending limb. PRR also promotes K+ secretion in response to K+loading through extra-adrenal aldosterone(Aldo)produc?tion. Overactivation of renal PRR contributes to the pathogenesis of hypertension induced by angiotensin Ⅱ infusion and fructose/salt. Overall,PRR has emerged as a new regulator of physiological and pathophysiological processes in the kidney.
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The renin-angiotensin system is an important body fluid regulation system in the human body,and it normally plays a significant role in the normal development and homeostatic regulation of the cardio-vascular system,the maintenance of electrolyte and body fluid balance,and the regulation of blood pressure.The (pro)renin receptor[(P)RR ] was been discovered as an important novel component of the renin-angiotensin system.It binds both prorenin and renin in tissues.(P)RR is widely expressed in human body,including kidney, brain,heart and placenta.It has been proved that the activated(P)RR participates in the activation of multiple in-tracellular signaling pathways and plays an important role in the pathogenesis of diabetic complications,hyperten-sion,heart failure and myocardial fibrosis.This review mainly summarizes the research progress of expression and function of(pro)renin receptor in the heart.
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Objective: To establish the cardio-renal syndrome (CRS) model by coarctation of abdominal aorta (CAA) with renal ischemia reperfusion injury (RIRI), and to observe the mRNA expression of pro-renin receptor [(P)RR] in experimental rats. Methods: A total of 42 Wistar rats were randomly divided into 4 groups: Sham group, CAA group, RIRI group and CAA+RIRI group.n=10 in each group, 2 rats died during the modeling and all animals were treated for 16 weeks. Blood levels of BNP, creatinine (Cr), urea nitrogen (BUN), the activity of rennin, the contents of angiotensin-I (AT-I), AT-II and aldosterone were examined by laboratory test. The diastolic end inter-ventricular septum thickness (DEIVST), DELVPT, LVEF, ventricular weight index (VWI) and cardiac weight index were detected by small animal echocardiography. The histological changes of myocardium and kidney tissue were measured by HE staining, and the mRNA expressions of pro-renin receptor in myocardium and kidney tissues were measured by RT-PCR. Results: Compared with Sham group, blood levels of BNP were increased in the other 3 groups,P0.05. Compared with CAA group, CAA+RIRI group had more obvious changes of DEIVST and LVEF,P<0.01. Compared with RIRI group, CAA+RIRI group had more obvious ventricular hypertrophy, higher VWI and cardiac weight index, allP<0.05. HE staining presented that CAA+RIRI group had broadening of myocardial cell bundle space, decreased left renal index, severe tubular atrophy and partial glomerular atrophy. RT-PCR demonstrated that compared with Sham group, the mRNA expressions of pro-renin receptor in myocardium and kidney tissues were decreased in the other 3 groups. Conclusion: Combined CAA+RIRI method may damage the cardial and renal tissues at the same time which was more severe than either CAA or RIRI. While CAA+RIRI model has better controllability and higher consistency that provides a methodological reference for pro-renin receptor in treating CRS in experimental rat’s model.
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Objective: A direct renin-inhibitor (DRI), aliskiren, was administered to anuric patients to investigate whether it can be a new optional therapy against hypertension in hemodialysis (HD) patients. Patients: The patients that received aliskiren comprised 8 males and 2 females with a mean ± SD age of 63 ± 8 years (43-72 years). They were exposed to dialysis therapy for 118 ± 73 months (8-251 months), with diabetes mellitus in 4 cases, chronic glomerulonephritis in 4 cases, and other diagnoses in 2 cases. Methods: After the plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured before an HD session, aliskiren, 150 mg as an initial dose, was administered to the patients. PRA and PAC were also examined a week after initiating aliskiren. The blood pressure (BP) levels at the start of each HD session for a period of 2 weeks (6 HD sessions) were compared between before and after administration of aliskiren. The change of doses in other antihypertensive agents was also counted. Results: The averaged reduction of mean blood pressure was 4 ± 5 mmHg, and doses of antihypertensives other than aliskiren were reduced in 4 patients. Of the examined parameters, only the reduction rate of PRA x PAC seemed correlated with the BP lowering effect of aliskiren, which was calculated as the sum of the mean BP reduction in mmHg and drug reduction with 1 tablet (capsule)/day considered to be 10 mmHg. Conclusion: A DRI, aliskiren, was effective even in anuric dialysis patients, and monitoring of PRA and PAC was valuable for selecting cases responsive to aliskiren.
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The renin-angiotension system (RAS) plays an important role in cardiovascular and renal physiology and diseases. Recent discoveries of prorenin and prorenin receptor add new contents to RAS. Renin and prorenin binding to the prorenin receptor not only target and facilitate angiotensin generation but also lead to activation of prorenin receptor signal transduction pathways, which is distinct from classical RAS signaling. In this paper, the construction, function and signal trasduction of prorenin, prorenin receptor and handle region peptide are reviewed.