Ang-(1-7) attenuates podocyte injury induced by high glucose in vitro

ABSTRACT Objective: The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN. Materials and methods: The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN in vitro, a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively. Results: The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 μM. Conclusion: This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.

Effects of Intestinal Flora and Local Renin-angiotensin System on Diabetic Nephropathy and Traditional Chinese Medicine Intervention： A Review / 中国实验方剂学杂志

Diabetic nephropathy （DN） is a common clinical complication of diabetes， the main cause of end-stage renal disease （ESRD）， and a key determinant of survival in diabetic patients. The pathogenesis of DN is complex， and it is currently believed to be associated with hemodynamic abnormalities， intestinal flora disturbances， glucose and lipid metabolism disorders， oxidative stress， genetic susceptibility， and protein non-enzymatic glycosylation. The local renin-angiotensin system （RAS） has always been the core of the pathogenic and progressive changes of DN. Once activated， it will induce the massive release of oxygen free radicals in the blood vessels， damage the endothelial function， and affect the microcirculation of the body. The recent studies demonstrate that intestinal flora and its metabolites may affect the occurrence and development of DN by activating or antagonizing the local RAS. Compared with western medicine treatment， traditional Chinese medicine （TCM） has the advantages of multiple targets and little toxic and side effects. Many TCM scholars have found that single herbs， their active ingredient extracts， and TCM compound prescriptions can improve kidney function by regulating the local RAS or intestinal flora. Specifically， the Chinese medicinal materials tonifying spleen （Codonopsis Radix， Dioscoreae Rhizoma， Atractylodis Macrocephalae Rhizoma， and Poria）， replenishing kidney （Rehmanniae Radix Praeparata， Corni Fructus， and Pseudostellariae Radix）， and activating blood， resolving stasis， and dredging collaterals （Hirudo， Salviae Miltiorrhizae Radix et Rhizoma， and Angelicae Sinensis Radix） have the regulatory effect. This article summarizes the roles of intestinal flora and local RAS in the occurrence and development of DN， and analyzes the animal experiments or clinical trials of TCM intervention in DN in recent years， aiming to provide more therapies and a theoretical basis for the treatment of DN with integrated TCM and Western medicine.

Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Effect of Anti-Renin Angiotensin System Drugs in Tumors / 医药导报

Initially,the renin-angiotensin system (RAS) was considered to play an important role in regulating cardiovascular function and maintaining the balance of water and electrolyte.Based on this,several targeted drugs in the treatment of hypertension were developed.With the large-scale clinical apphcation of these drugs,RAS inhibitors are found to has a significant inhibitory effect on some of the tumor development,which reveals the RAS function in cell proliferation,differentiation,angiogenesis and tumor occurrence.In this paper,the important physiological ftmction of RAS in tumor occurrence and development were reviewed.

The Effect of Withdrawal of Angiotensin II Blockers on Serum Creatinine and Potassium in Patients with Chronic Kidney Diseases / 대한신장학회잡지

BACKGROUND: Renin-ngiotensin system (RAS) blockers have been used to delay the progression of various renal diseases, but these medications cause hyperkalemia and the elevation of serum creatinine which impede the continuation of the medications. So far, there have been no data on the changes of serum creatinine or serum potassium after withdrawal of the RAS blockers. METHODS: We reviewed medical records of 60 patients who stopped the RAS blockers due to the elevation of serum creatinine or hyperkalemia between March 1995 and May 2005. They were assigned to either the elevated creatinine group or the hyperkalemia group according to the cause of the withdrawal. RESULTS: In the elevated creatinine group (n=37), the serum creatinine and GFR values at the point of withdrawal were 4.0+/-1.8 mg/dL and 18.2+/-10.4 mL/min/1.73m2, respectively. After discontinuation of the medications, a decrease in serum creatinine and an increase in GFR were noted at one month. After one month, however, serum creatinine increased continuously up to 6 months. Serum potassium levels decreased significantly after the drug withdrawal until the end of the study period. In the hyperkalemia group (n=23), the serum creatinine and serum potassium values at the point of withdrawal were 3.0+/-1.0 mg/dL and 6.4+/-0.4 mEq/L, respectively. A significant decrease in serum potassium was also noted after the withdrawal and this decrease lasted up to 6 months. But the transient decrease of serum creatinine, observed in the creatinine group, was not seen in this group. CONCLUSION: It was found that there was a beneficial effect on serum creatinine and GFR immediately after the withdrawal of RAS blockers only when they were stopped due to elevation of the serum creatinine concentration. The serum potassium levels were consistently decreased after the withdrawal of RAS blockers in both elevated creatinine and hyperkalemia groups.

Prognostic Factors in Children with Henoch-Schonlein Purpura Nephritis

PURPOSE: The long term disease course and prognostic factors were evaluated in childhood Henoch-Schonlein purpura nephritis(HSPN). METHODS: A total of 75 children(44 boys and 31 girls) with HSPN were included in this study. The onset age was 8.0+/-3.1 years(2.3-15.3 years), and the follow-up period was 4.3+/-3.6 years(1.0-17.1 years). Kidney biopsy was done in 24 children(32%). Initial clinical and laboratory findings were evaluated. In addition, polymorphisms of the renin angiotensin system(RAS) genes(insertion/deletion in intron 16 of ACE gene, M235T in AGT gene, and A1166C in AGTR gene) were analysed. The initial and last clinical states were classified into 4 groups as follows:A, normal; B, minor urinary abnormalities; C, active renal disease (nephrotic-range proteinuria and/or hypertension with serum creatinine < or =1.5 mg/dL); D, renal insufficiency. RESULTS: At the onset, the clinical states of the patients were B in 26(35%), C in 46(61%), and D, in 3(4%). The distribution of the RAS gene polymorphism of HSPN were not different from that of 100 healthy control subjects. At the last follow-up, the clinical states of the patients were A in 23(31%), B in 38(50%), C in 9(12%), and D in 5(7%). A multiple logistic regression identified age at the onset and initial urine protein excretion as significant prognostic factors. Analysis of genotypes of the 3 RAS genes as prognostic values revealed no statistical significance. CONCLUSION: Older age at onset and severe proteinuria were identified as poor prognostic factors of childhood HSPN. Implication of the RAS gene polymorphism in HSPN could not be validated in this small-scale retrospective study.

The Effect of Rennin-angiotensin System on Endothelin-1 and Nitric Oxide in Rat Glomerulosclerosis / 中国医师杂志

Objective To investigate the correlation among glomerulosclerosis and endothelin-1(ET-1) and nitric oxide(NO), and the effect of blocking renin-angiotensin system(RAS) on rat glomerulosclerosis. Methods 30 SD rats underwent unilateral nephrectomy plus adriamycin (6mg/kg) injection through caudal vein to establish rat glomerulosclerosis models. These rats were divided randomly into glomerulosclerosis group (group D), Benazepril treatment group (group DB) and Losartan treatment group (group DL). Another 10 SD rats served as sham-operation group (group C). 6 weeks after treamtent, the mRNA and protein expressions of ET-1 and iNOS in renal cortex were detected using RT-PCR and Western blotting analysis respectively, and the content of fibronectin(Fn) was measured using immunohistochemical method. Results Group D occurred massive proteinuria, hypoalbuminemia and hypercholesterolemia, which had significant differences compared with group C (P