Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.

BACKGROUND: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. METHODS: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)-SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) (SIRT2-TG) mice SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. RESULTS: Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)- induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. CONCLUSIONS: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II-induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

The Protective Effect of Vitexin on Hypertensive Nephropathy Rats.

INTRODUCTION: Vitexin is a natural flavonoid compound extracted from Vitex leaves or seeds, exhibiting various pharmacological activities including anticancer, antihypertensive, anti-inflammatory, and spasmolytic effects. However, its protective effects on hypertensive nephropathy (HN) and the underlying mechanisms remain unclear. METHODS: Spontaneous hypertension rats were fed a high-sugar and high-fat diet for 8 weeks to induce the disease HN model. From the 5th week, the rats were administered vitexin via gavage. Blood pressure was measured biweekly using the tail-cuff method. Histopathological changes were assessed using HE staining, and biochemical analyses were performed to evaluate the effects of vitexin on HN rats. The underlying mechanisms of vitexin treatment were investigated through western blotting. RESULTS: The data demonstrated that vitexin significantly lowered systolic, diastolic, and mean arterial pressures and ameliorated histopathological changes in HN rats. Biochemical analyses revealed that vitexin reduced the levels of creatinine (Cr), blood urea nitrogen (BUN), total cholesterol (TC), triglycerides (TG), total protein (TP), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and advanced glycation end products (AGEs), while increasing the levels of albumin (ALB) and superoxide dismutase (SOD). Western blotting results indicated that vitexin treatment decreased the expression of TNF-α, IL-6, and nuclear factor kappa-B (NF-κB), while increasing the expression of SOD. CONCLUSION: The findings of this study suggest that vitexin exerts protective effects against HN, providing pharmacological evidence for its potential use in HN treatment.

α-Mangostin reduces hypertension in spontaneously hypertensive rats and inhibits EMT and fibrosis in Ang II-induced HK-2 cells.

Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.

VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway.

Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.

Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023.

Hypertensive nephropathy continues to be a major cause of end-stage renal disease and poses a significant global health burden. Despite the staggering development of research in hypertensive nephropathy, scientists and clinicians can only seek out useful information through articles and reviews, it remains a hurdle for them to quickly track the trend in this field. This study uses the bibliometric method to identify the evolutionary development and recent hotspots of hypertensive nephropathy. The Web of Science Core Collection database was used to extract publications on hypertensive nephropathy from January 2000 to November 2023. CiteSpace was used to capture the patterns and trends from multi-perspectives, including countries/regions, institutions, keywords, and references. In total, 557 publications on hypertensive nephropathy were eligible for inclusion. China (n = 208, 37.34%) was the most influential contributor among all the countries. Veterans Health Administration (n = 19, 3.41%) was found to be the most productive institution. Keyword bursting till now are renal fibrosis, outcomes, and mechanisms which are predicted to be the potential frontiers and hotspots in the future. The top seven references were listed, and their burst strength was shown. A comprehensive overview of the current status and research frontiers of hypertensive nephropathy has been provided through the bibliometric perspective. Recent advancements and challenges in hypertensive nephropathy have been discussed. These findings can offer informative instructions for researchers and scholars.

Ferroptosis and secondary nephrosis. / é“æ­»äº¡ä¸Žç»§å‘æ€§è‚¾è„ç— .

Secondary nephrosis is a series of chronic kidney diseases secondary to other underlying diseases, mainly manifesting as structural and functional abnormalities of the kidneys and metabolic disorders. It is one of the important causes of end-stage renal disease, with high morbidity and significant harm. Iron is an essential metal element in human cells, and ferroptosis is a non-traditional form of iron-dependent cell death, and its main mechanisms include iron accumulation, lipid metabolism disorders, abnormal amino acid metabolism, and damage to the antioxidant system. Recently studies have found that ferroptosis is involved in the occurrence and progression of secondary nephrosis, and the mechanism of ferroptosis in different secondary nephrosis vary. Therefore, an in-depth and systematic understanding of the association between ferroptosis and secondary nephrosis, as well as their specific regulatory mechanisms, can provide a theoretical basis for the diagnosis, prevention, treatment, and prognosis assessment of secondary nephrosis, laying the foundation for exploring new clinical therapeutic targets for secondary nephrosis.

Proteomics to Metabolomics: A New Insight into the Pathogenesis of Hypertensive Nephropathy.

BACKGROUND: Hypertensive nephropathy (HN) is a high-burden disorder and a leading cause of end-stage renal disease. Despite huge investigations, the underlying mechanisms are yet largely unknown. Systems biology is a promising approach to providing a comprehensive insight into this complex disorder. METHODS: Proteome profiles of kidney tubulointerstitium and outer and inner cortex from a rat model of HN were retrieved from the proteomics identification database, and the quality of the datasets was assessed. Proteins that exhibited differential expression were detected and their interactions were analyzed in the kidney sub-compartments. Furthermore, enzymes were linked to the attributed metabolites. Functional enrichment analyses were performed to identify key pathways and processes based on the differentially expressed proteins and predicted metabolites. RESULTS: Proteasome-mediated protein degradation, actin cytoskeleton organization, and Rho GTPase signaling pathway are involved in the pathogenesis of HN. Furthermore, tissue hypoxia and dysregulated energy homeostasis are among the key underlying events. The metabolism of purine and amino acids is also affected in HN. CONCLUSION: Although the proposed pathogenic mechanisms remain to be further validated in experimental studies, this study contributes to the understanding of the molecular mechanisms of HN through a systematic unsupervised approach. Considering the significant alterations of metabolic pathways, HN can be viewed as an "acquired error of metabolism."

GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy.

Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.

Hypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons.

Hypertension is one of the most common risk factors for developing chronic cardiovascular diseases, including hypertensive nephropathy. Within the glomerulus, hypertension causes damage and activation of mesangial cells (MCs), eliciting the production of large amounts of vasoactive and proinflammatory agents. Accordingly, the activation of AT1 receptors by the vasoactive molecule angiotensin II (AngII) contributes to the pathogenesis of renal damage, which is mediated mostly by the dysfunction of intracellular Ca2+ ([Ca2+]i) signaling. Similarly, inflammation entails complex processes, where [Ca2+]i also play crucial roles. Deregulation of this second messenger increases cell damage and promotes fibrosis, reduces renal blood flow, and impairs the glomerular filtration barrier. In vertebrates, [Ca2+]i signaling depends, in part, on the activity of two families of large-pore channels: hemichannels and pannexons. Interestingly, the opening of these channels depends on [Ca2+]i signaling. In this review, we propose that the opening of channels formed by connexins and/or pannexins mediated by AngII induces the ATP release to the extracellular media, with the subsequent activation of purinergic receptors. This process could elicit Ca2+ overload and constitute a feed-forward mechanism, leading to kidney damage.

Inhibition of YAP activation attenuates renal injury and fibrosis in angiotensin II hypertensive mice.

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1ß, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor ß, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II-induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Effect of patient-centred self-management programme on mental health, self-efficacy and self-management of patients with hypertensive nephropathy: A randomised controlled trial.

AIM AND OBJECTIVES: To evaluate the effect of patient-centred self-management programme on mental health, self-efficacy and self-management of patients with hypertensive nephropathy. BACKGROUND: If the symptoms of hypertension are not well-controlled, deterioration of renal function will accelerate and evolve into hypertensive nephropathy. DESIGN: A randomised single-blind trial. This article follows the requirements of CONSORT statement. METHODS: The experimental group (n = 35) after pre-test used patient-centred self-management programme once a week for a total of 4 weeks and the intervention effect was measured after 3 months for post-test. Contrarily, the traditional care was employed for the control group (n = 35). The measuring outcomes included mental health, self-efficacy and self-management. Trial registry is listed under https://clinicaltrials.gov/ with Identifier No. NCT04633993. RESULTS: After the intervention, the average score of mental health for the experimental group was 20.79 (SD = 0.82) which was higher than the 19.27 points for the control group (SD = 0.77) and showed a significant difference (F = 8.31, p = .005, partial eta2  = 0.133). In terms of self-efficacy, the average score for the experimental group was 214.13 (SD = 6.40), which was higher than the 189.58 points for the control group (SD = 6.03) and exhibited a significant difference (F = 11.82, p = .001, partial eta2  = 0.197). Regarding self-management, the average score of the experimental group was 75.12 (SD = 2.29) which was significantly higher than the 68.80 points of the control group (SD = 2.43) (F = 11.17, p = .001, partial eta2  = 0.190). CONCLUSIONS: In addition to promoting mental health of individual cases, this intervention also increases their self-confidence in disease control and improves their self-management on diseases. RELEVANCE TO CLINICAL PRACTICE: The intervention provides an effective option for clinical care workers as a replacement for or supplement to the traditional care.

Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy.

Angiotensin-converting enzyme-2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1-7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II-induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild-type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7-28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1-ERK1/2-Smad3 and NF-κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II-induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1-7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.

Bromodomain-containing protein 4 contributes to renal fibrosis through the induction of epithelial-mesenchymal transition.

Fibrosis is a common pathology in renal disease. Hypertensive nephropathy (HN) is one of the most common secondary nephropathies that often progresses to severe renal fibrosis with limited treatment options beyond hypertension control. Bromodomain-containing protein 4 (Brd4) was recently recognized as a target in signaling pathways that underlie the pathologies of inflammatory diseases and tumors. A recently developed inhibitor of Brd4, JQ1, has been shown to exert antifibrotic effects and is being clinically explored as an anti-inflammatory and antitumor drug. Here, using human kidney biopsies and Angiotensin II-induced mouse fibrotic kidney samples, we show that Brd4 was upregulated in renal tissue from HN patients and hypertensive mouse models. In mice, JQ1 alleviated Angiotensin II-induced kidney fibrosis and blocked epithelial-mesenchymal transition (EMT) by altering the expression of EMT-related proteins. Using an in vitro model of HK2 cells exposed to Angiotensin II, we also demonstrated that JQ1 suppressed the protein expression of fibrotic genes in these cells. These results further implicate Brd4 in the fibrotic response in HN and reveal that Brd4 is a potential antifibrotic target. BET inhibitors are currently being investigated in clinical trials as antitumor agents and show potent pharmacological effects. Our findings suggest that BET inhibitors may also be potential translational therapies for HN.

Aetiology of chronic kidney disease and risk factors for disease progression in Chinese subjects: A single-centre retrospective study in Beijing.

AIM: To assess the aetiological factors of chronic kidney disease (CKD) and factors associated with disease progression. METHODS: Single-centre retrospective study evaluating thorough electronic medical records of patients diagnosed with CKD at Peking University People's Hospital (April 2010-April 2015). The objectives were to identify the aetiological factors of CKD in Chinese patients and risk factors associated with CKD progression. RESULTS: Of 15 425 CKD patients, 12 380 had aetiology recorded. The leading aetiologies associated with CKD were chronic glomerulonephritis (CGN; 36.8%), hypertensive nephropathy (HTN; 28.5%) and diabetic nephropathy (DN; 27.1%). CGN was most common in patients with early stage disease (stages 1-2); DN and HTN were common in advanced-stages (stages 3-4). In a longitudinal subcohort of 2923 patients with ≥6-month follow-up, 19.6% experienced CKD progression. Patients with CKD progression were significantly older in age and had a greater number of comorbidities and laboratory anomalies, and were more likely to have DN (40.5%) and CGN (40.5%) than HTN (5.5%) at baseline than patients without progression. In a multivariate analysis, factors associated with disease progression included macro- and micro-albuminuria, anaemia, hyperkalaemia, hyperphosphataemia, metabolic acidosis, CKD stage 4 and type 2 diabetes mellitus (T2DM). CONCLUSION: This study identified CGN, DN and HTN as the leading aetiological factors for CKD in Chinese patients. DN was a strong predictor of faster disease progression, with albuminuria (a complication of T2DM) associated with highest risk for disease progression.

Identification of biomarkers and pathways in hypertensive nephropathy based on the ceRNA regulatory network.

BACKGROUND: Hypertensive nephropathy (HTN) is a kind of renal injury caused by chronic hypertension, which seriously affect people's life. The purpose of this study was to identify the potential biomarkers of HTN and understand its possible mechanisms. METHODS: The dataset numbered GSE28260 related to hypertensive and normotensive was downloaded from NCBI Gene Expression Omnibus. Then, the differentially expressed RNAs (DERs) were screened using R limma package, and functional analyses of DE-mRNA were performed by DAVID. Afterwards, a ceRNA network was established and KEGG pathway was analyzed based on the Gene Set Enrichment Analysis (GSEA) database. Finally, a ceRNA regulatory network directly associated with HTN was proposed. RESULTS: A total of 947 DERs were identified, including 900 DE-mRNAs, 20 DE-lncRNAs and 27 DE-miRNAs. Based on these DE-mRNAs, they were involved in biological processes such as fatty acid beta-oxidation, IRE1-mediated unfolded protein response, and transmembrane transport, and many KEGG pathways like glycine, serine and threonine metabolism, carbon metabolism. Subsequently, lncRNAs KCTD21-AS1, LINC00470 and SNHG14 were found to be hub nodes in the ceRNA regulatory network. KEGG analysis showed that insulin signaling pathway, glycine, serine and threonine metabolism, pathways in cancer, lysosome, and apoptosis was associated with hypertensive. Finally, insulin signaling pathway was screened to directly associate with HTN and was regulated by mRNAs PPP1R3C, PPKAR2B and AKT3, miRNA has-miR-107, and lncRNAs SNHG14, TUG1, ZNF252P-AS1 and MIR503HG. CONCLUSIONS: Insulin signaling pathway was directly associated with HTN, and miRNA has-miR-107 and lncRNAs SNHG14, TUG1, ZNF252P-AS1 and MIR503HG were the biomarkers of HTN. These results would improve our understanding of the occurrence and development of HTN.

The correlation of circulating miR-29b and inflammatory markers with albuminuria in hypertensive patients.

AIMS: Circulating miR-29b and inflammatory process play a vital role in hypertension and hypertensive nephropathy. The aim of the present study was to investigate the association of circulating miR-29b and inflammatory markers with albuminuria and assess the predictive value of circulating miR-29b for albuminuria in essential hypertension. METHODS: This cross-sectional study was continuously enrolled 150 subjects and were divided into three groups based on random urinary albumin/creatinine ratio (UACR, mg/g), the patients with ACR<30 mg/g were classified as normal albuminuria, the values of 30< ACR<300 was defined as micro-albuminuria while the group with ACR over 300 mg/g are macro-albuminuria. Circulating miR-29b was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Multivariate logistic regression and area under the ROC curve (AUC) were used. RESULTS: We found miR-29b, C-reactive protein, and transforming growth factor-ß1 (TGF-ß1) in macro-albuminuria group were significantly higher than those in the micro-albuminuria and normal albuminuria group. The level of miR-29b was positively associated with TGF-ß1, C-reactive protein, and UACR, while negatively related to glomerular filtration rate. Circulating miR-29b was a significant independent determinant factor for albuminuria. CONCLUSION: Our results provided a clinical evidence of a positive association between circulating miR-29b, inflammatory markers, and UACR, and implied miR-29b was a significant independent determinant factor for albuminuria.

[Network Meta-analysis of Huoxue Huayu Chinese medicine injections on hypertensive nephropathy].

To assess the clinical efficacy of Huoxue Huayu Chinese medicine injections on hypertensive nephropathy by using Network Meta-analysis method. The relative randomized controlled trials(RCTs) of Huoxue Huayu Chinese medicine injections on hypertensive nephropathy were retrieved from CNKI, WanFang, VIP, SinoMed, PubMed, Cochrane Library and Web of Science in November 2019. Two researchers independently conducted literature screening, data extraction and quality evaluation. The data was analyzed by RevMan 5.3, Stata 15.1, ADDIS 1.16.8 software. Finally, 4 518 patients in 50 RCTs were included, involving 5 kinds of Huoxue Huayu Chinese medicine injections. The five Chinese medicine injections were Breviscapine Injection, Danhong Injection, Sodium Tanshinone Ⅱ_A Sulfonate Injection, Ginkgo Dipyridamole Injection, and Salvianolate Injection. Meta-analysis showed that, in terms of renal function protection, urine protein quantification and serum creatinine of each Chinese medicine injections combined with conventional Western medicine group, except Salvianolate Injection combined with conventional Western medicine group, was significantly lower than those of the conventional Western medicine treatment group. Ginkgo Dipyridamole Injection combined with conventional Western medicine had the best effect in reducing urine protein, and Danhong Injection combined with conventional Western medicine had the best effect in reducing serum creatinine. In terms of blood pressure control, the blood pressure of each Chinese medicine injections combined with conventional Western medicine group, except Breviscapine Injection combined with conventional Western medicine group, was significantly lower than that of conventional Western medicine treatment group. Salvianolate Injection combined with conventional Western medicine had the best effect in reducing blood pressure. In terms of safety, no serious adverse reactions were found in all studies. The five kinds of Huoxue Huayu Chinese medicine injections combined with conventional Western medicine had significantly advantages in the treatment of hypertensive nephropathy. Ginkgo Dipyridamole Injection combined with conventional Western medicine is most likely to be the optimal therapy. However, limited by the quantity and quality of the documents included, the conclusion of this study still needs to be verified by more high-quality, multi-center and large-sample RCT.

Naringenin Ameliorates Renovascular Hypertensive Renal Damage by Normalizing the Balance of Renin-Angiotensin System Components in Rats.

Background: Naringenin, a member of the dihydroflavone family, has been shown to have a protective function in multiple diseases. We previously demonstrated that naringenin played a protective role in hypertensive myocardial hypertrophy by decreasing angiotensin-converting enzyme (ACE) expression. The kidney is a primary target organ of hypertension. The present study tested the effect of naringenin on renovascular hypertensive kidney damage and explored the underlying mechanism. Methods and Results: An animal model of renovascular hypertension was established by performing 2-kidney, 1-clip (2K1C) surgery in Sprague Dawley rats. Naringenin (200 mg/kg/day) or vehicle was administered for 10 weeks. Blood pressure and urinary protein were continuously monitored. Plasma parameters, renal pathology and gene expression of nonclipped kidneys were evaluated by enzyme-linked immunosorbent assay, histology, immunohistochemistry, real-time polymerase chain reaction, and Western blot at the end of the study. Rats that underwent 2K1C surgery exhibited marked elevations of blood pressure and plasma Ang II levels and renal damage, including mesangial expansion, interstitial fibrosis, and arteriolar thickening in the nonclipped kidneys. Naringenin significantly ameliorated hypertensive nephropathy and retarded the rise of Ang II levels in peripheral blood but had no effect on blood pressure. 2K1C rats exhibited increases in the ACE/ACE2 protein ratio and AT1R/AT2R protein ratio in the nonclipped kidney compared with sham rats, and these increases were significantly suppressed by naringenin treatment. Conclusions: Naringenin attenuated renal damage in a rat model of renovascular hypertension by normalizing the imbalance of renin-angiotensin system activation. Our results suggest a potential treatment strategy for hypertensive nephropathy.

MiR-101a ameliorates AngII-mediated hypertensive nephropathy by blockade of TGFß/Smad3 and NF-κB signalling in a mouse model of hypertension.

Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR-101a in relieving angiotensin II (Ang II)-mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28-day AngII infusion. Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated. Dual luciferase reporter assay was used to explore the target of miR-101a. mRNA levels of miR-101a, TGFßRI, fibrotic markers (Collagen I and α-SMA) and pro-inflammatory cytokines (IL-1ß and TNF-α) were determined by real-time PCR. Protein levels of TGFßRI, Collagen I, α-SMA, IL-1ß, TNF-α, t-p65, P-p65, t-Smad3, P-Smad3, t-IκBα and P-IκBα were detected by western blot. MiR-101a mimics significantly improved GFR and inhibited AngII-induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR-101a mimics partially abolished AngII-induced increase in the mRNA and protein level of fibrotic markers by targeting TGFßRI and inhibiting TGFß/Smad3 pathway. Moreover, TGFßRI inhibitor galunisertib inhibited AngII-mediated renal injury in mice with hypertensive nephropathy. Additionally, miR-101a overexpression blocked AngII-induced up-regulation of pro-inflammatory markers via suppressing NF-κB pathway. MiR-101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFß/Smad3 and NF-κB signalling pathways.