Dataset Information

Hsa_circRNA_0045861 promotes renal injury in ureteropelvic junction obstruction via the microRNA-181d-5p/sirtuin 1 signaling axis

ABSTRACT:

Background

Ureteropelvic junction obstruction (UPJO) is one of the most common causes of hydronephrosis in children. This study explored the effects and the regulatory mechanisms of the circular RNA (circRNA) hsa_circRNA_0045861 (circRNA_0045861) in UPJO.

Methods

RNA sequencing was used to identify the differentially expressed circRNAs in UPJO. The effects of circRNA_0045861 on renal cell apoptosis was investigated by flow cytometry and Western blot analysis. Furthermore, we used bioinformatics methods to predict the possible target genes of circRNA_0045861. Fluorescence in-situ hybridization and dual-luciferase reporter assays were performed to validate the target genes of circRNA_0045861. Finally, we evaluated the effects of circRNA_0045861 target gene miR-181d-5p on UPJO-induced renal fibrosis in vivo.

Results

RNA sequencing identified 63 upregulated and 64 downregulated circRNAs in UPJO patients. The expression of circRNA_0045861 was significantly elevated in kidney damage both in vivo and in vitro. Silencing circ_0045861 inhibited transforming growth factor (TGF)-β1-induced apoptosis in vitro in human kidney 2 (HK-2) cells. Furthermore, circ_0045861 was shown to directly interact with the microRNA miR-181d-5p and regulate the expression of sirtuin 1 (SIRT1), thereby promoting the progression of apoptosis and renal injury. In addition, overexpression of miR-181d-5p inhibited cell apoptosis and renal fibrosis in a mouse model through downregulating the SIRT1/p53 pathway.

Conclusions

Circ_0045861 may be a novel candidate circRNA in the pathogenesis of UPJO by acting as a pro-apoptotic factor via the miR-181d-5p/SIRT1 axis.

SUBMITTER: Fan X

PROVIDER: S-EPMC8576705 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceExtracellular matrix proteins and enzymes involved in degradation have been found to be associated with tissue fibrosis and ureteropelvic junction obstruction (UPJO). In this study we developed a promising urinary biomarker model which can identify reduced renal function in UPJ obstruction patients. This can potentially serve as a non-invasive way to enhance surgical decision making for patients and urologists.ObjectiveWe sought to develop a predictive model to identify UPJO patients at risk for reduced renal function.DesignProspective cohort study.SettingPre-operative urine samples were collected in a prospectively enrolled UPJO biomarker registry at our institution. Urinary MMP-2, MMP-7, TIMP-2, and NGAL were measured as well as clinical characteristics including hydronephrosis grade, differential renal function, t1/2, and UPJO etiology.ParticipantsChildren who underwent pyeloplasty for UPJO.Main outcome measurementPrimary outcome was reduced renal function defined as MAG3 function <40%. Multivariable logistic regression was applied to identify the independent predictive biomarkers in the original Training cohort. Model validation and generalizability were evaluated in a new UPJO Testing cohort.ResultsWe included 71 patients with UPJO in the original training cohort and 39 in the validation cohort. Median age was 3.3 years (70% male). By univariate analysis, reduced renal function was associated with higher MMP-2 (p = 0.064), MMP-7 (p = 0.047), NGAL (p = 0.001), and lower TIMP-2 (p = 0.033). Combining MMP-7 with TIMP-2, the multivariable logistic regression model predicted reduced renal function with good performance (AUC = 0.830; 95% CI: 0.722-0.938). The independent testing dataset validated the results with good predictive performance (AUC = 0.738).Conclusions and relevanceCombination of urinary MMP-7 and TIMP-2 can identify reduced renal function in UPJO patients. With the high sensitivity cutoffs, patients can be categorized into high risk (aggressive management) versus lower risk (observation).

Project description:Introduction stating the aim of the study: Robot-assisted laparoscopic pyeloplasty (RALP) is gaining acceptance among pediatric urologists. Few studies have evaluated the retroperitoneal approach for RALP. We share our experience from the first 2 years of a multidisciplinary pediatric robotic program in our center. Patients (or Materials) and Methods: We performed a retrospective analysis of prospectively collected data of children undergoing RALP for ureteropelvic junction obstruction (n = 50). Diagnosis was confirmed by ultrasound and Tc-99m mercaptoacetyltriglycine renal scan or MRI; the same criteria were used to evaluate outcome. Surgical approach was chosen according to a specific algorithm. Transperitoneal approach (n = 13) was reserved for horseshoe kidney, ectopic kidney, and redo surgery. We analyzed the 37 cases performed by a lateral retroperitoneal approach. Dismembered pyeloplasty was done for all cases and anastomosis was performed using a running monofilament 6/0 absorbable suture. All were drained by double J stent. Patient data, operating room parameters and postoperative course were recorded. Results: The median age was 7.9 years (5.1-13.8); the youngest was 2 years old. The median weight was 23 kg (17-41) with the smallest weighing 12.4 kg. Aberrant crossing vessels were present in 18 children. Median set-up time, from skin incision until the end of the 4-port insertion, was 33 min (29-48). Median surgeon's console time was 151 min (136-182). No conversion to an open procedure was necessary. The postoperative course was free of complications, except urinary tract infection in 6 children. All but 4 patients were discharged on day one. Median follow-up was 9 months (5-13). Redo pyeloplasty was not required. Practical training of other colleagues was possible after 10 cases performed by the same surgeon. Conclusion: These preliminary results suggest that retroperitoneal RALP in children is feasible, safe and effective. It is an excellent option with ideal anatomical exposure. Longer term results as well as continued practice will identify and overcome any challenges and enable surgical mastery of this procedure which is still evolving.

Project description:BackgroundMultiple surgical treatment options are available for the treatment of ureteropelvic junction obstruction (UPJO). The aim of this study is to compare the most frequently used technics in a comprehensive network approach.MethodsA systematic literature search of the EMBASE, MEDLINE and COCHRANE libraries was conducted in January 2018. Publications were included that evaluated at least two of the following surgical techniques: open pyeloplasty (OP), endopyelotomy (EP), laparoscopic (LP) and robot assisted pyeloplasty (RP). Main outcomes were operative success, complications, urinary leakage, re-operation, transfusion rate, operating time, and length of stay. Network meta-analyses with random effects models simultaneously assessed effectiveness of all surgical techniques.ResultsA total of 26 studies including 3143 patients were analyzed. Compared with RP, EP and LP showed lower operative success rates (EP: OR?=?0.09, 95%CI:0.05-0.19; p <?0.001; LP: OR?=?0.51, 95%CI:0.31-0.84; p =?0.008). Compared with OP, LP and RP had lower risk for complications (LP: OR?=?0.62; 95%CI:0.41-0.95; p =?0.027; RP: OR?=?0.41; 95%CI:0.22-0.79; p =?0.007). Compared with RP, no significant differences were detected for urinary leakage or re-operation, transfusion rates. Compared with EP, RP yielded longer operating time (mean?=?102.87?min, 95%CI:41.79?min-163.95?min, p =?<?0.001). Further significant differences in operating times were detected when comparing LP to EP (mean?=?115.13?min, 95%CI:65.63?min-164.63?min, p =?<?0.001) and OP to EP (mean?=?91.96?min, 95%CI:32.33?min-151.58?min, p =?0.003).ConclusionsMultiple surgical techniques are available for treatment of UPJO. RP has the highest rates of operative success and as well as LP lower complication rates than OP. Although surgical outcomes are worse for EP, its operating time is shorter than OP, RP, and LP. Surgeons should consider these findings when selecting the optimal treatment method for individual patients.

Project description:Congenital anomalies of the urinary tract, and particularly of obstructive nephropathy such as ureteropelvic junction obstruction (UPJO) in infants, can later lead to chronic kidney disease and hypertension. Fundamental questions regarding underlying mechanisms remain unanswered. The aim of the present study was to quantitate the systemic amino acids metabolome in 21 UPJO infants requiring surgery (Group A) and 21 UPJO infants under conservative treatment (Group B). Nineteen healthy age-matched infants served as controls (Group C). Serum amino acids involved in several pathways and representative metabolites, including the L-arginine-derived nitric oxide (NO) metabolites nitrite and nitrate and the lipid peroxidation biomarker malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry (GC-MS) methods using their stable-isotope labeled analogs as internal standards after derivatization to their methyl esters N-pentafluoropropionic amides (amino acids) and to their pentafluorobenzyl derivatives (nitrite, nitrate, MDA). The concentrations of the majority of the biomarkers were found to be lower in Group A compared to Group B. Statistical analysis revealed clear differentiation between the examined study groups. Univariate statistical analysis highlighted serum homoarginine (q = 0.006), asymmetric dimethylarginine (q = 0.05) and malondialdehyde (q = 0.022) as potential biomarkers for UPJO infants requiring surgery. Group A also differed from Group B with respect to the diameter of the preoperative anterior-posterior renal pelvis (AP) as well as regarding the number and extent of inverse correlations between AP and the serum concentrations of the biomarkers. In Group A, but not in Group B, the AP diameter strongly correlated with hydroxy-proline (r = -0.746, p = 0.0002) and MDA (r = -0.754, p = 0.002). Our results indicate a diminished amino acids metabolome in the serum of UPJO infants requiring surgery comparing to a conservative group.