Ureteral Obstruction Research Articles

Dose-Dependent Nephroprotective Effects of an ALK5 Inhibitor in the Unilateral Ureteral Obstruction (UUO) Mouse Model of Kidney Fibrosis

Dose-Dependent Nephroprotective Effects of an ALK5 Inhibitor in the Unilateral Ureteral Obstruction (UUO) Mouse Model of Kidney Fibrosis

Global but Not Tubule Cell-Specific Knockout of STING Attenuates Kidney Injury in Mice with Unilateral Ureteral Obstruction

Global but Not Tubule Cell-Specific Knockout of STING Attenuates Kidney Injury in Mice with Unilateral Ureteral Obstruction

Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury

Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.

Kidney Hypoplasia Increases Kidney Injury following Reversal of Unilateral Ureteral Obstruction

Kidney Hypoplasia Increases Kidney Injury following Reversal of Unilateral Ureteral Obstruction

Unveiling the role of transgelin as a prognostic and therapeutic target in kidney fibrosis via a proteomic approach

Chronic kidney disease (CKD) progression involves tubulointerstitial fibrosis, a process characterized by excessive extracellular matrix accumulation. To identify potential biomarkers for kidney fibrosis, we performed mass spectrometry-based proteomic profiling of human kidney tubular epithelial cells and kidney tissue from a 5/6 nephrectomy rat model. Multidisciplinary analysis across kidney fibrosis models revealed 351 differentially expressed proteins associated with kidney fibrosis, and they were enriched in processes related to the extracellular matrix, kidney aging, and mitochondrial functions. Network analysis of the selected proteins revealed five crucial proteins, of which transgelin emerged as a candidate protein that interacts with known fibrosis-related proteins. Concordantly, the gene expression of transgelin in the kidney tissue from the 5/6 nephrectomy model was elevated. Transgelin expression in kidney tissue gradually increased from intermediate to advanced fibrosis stages in 5/6 Nx rats and mice with unilateral ureteral obstruction. Subsequent validation in kidney tissue and urine samples from patients with CKD confirmed the upregulation of transgelin, particularly under advanced disease stages. Moreover, we investigated whether blocking TAGLN ameliorated kidney fibrosis and reduced reactive oxygen species levels in cellular models. In conclusion, our proteomic approach identified TAGLN as a potential noninvasive biomarker and therapeutic target for CKD-associated kidney fibrosis, suggesting its role in modulating mitochondrial dysfunction and oxidative stress responses.

Attenuation of renal fibrosis in mice due to lack of bombesin receptor-activated protein homologue.

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-β1 (TGF-β1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.

Inhibition of Hyaluronan Synthesis Attenuates Tubulointerstitial Inflammation and Fibrosis in Murine Unilateral Ureteral Obstruction Model of CKD

Inhibition of Hyaluronan Synthesis Attenuates Tubulointerstitial Inflammation and Fibrosis in Murine Unilateral Ureteral Obstruction Model of CKD

Imperatorin Ameliorates Ferroptosis-Associated Cell Death, Inflammation, and Kidney Fibrosis in a Unilateral Ureteral Obstruction Mouse Model

Imperatorin Ameliorates Ferroptosis-Associated Cell Death, Inflammation, and Kidney Fibrosis in a Unilateral Ureteral Obstruction Mouse Model

Modulating Branched-Chain Amino Acid Catabolism: A New Approach to Ameliorate Cisplatin- and Unilateral Ureteral Obstruction (UUO)-Induced Kidney Injury

Modulating Branched-Chain Amino Acid Catabolism: A New Approach to Ameliorate Cisplatin- and Unilateral Ureteral Obstruction (UUO)-Induced Kidney Injury

Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease.

As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-β1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-β1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both invivo and invitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis invivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.

Collecting Duct Pro(Renin) Receptor Contributes to Unilateral Ureteral Obstruction-Induced Kidney Injury via Activation of the Intrarenal RAS.

Although the concept of the intrarenal renin-angiotensin system (RAS) in renal disease is well-described in the literature, the precise pathogenic role and mechanism of this local system have not been directly assessed in the absence of confounding influence from the systemic RAS. The present study used novel mouse models of collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) or renin together with pharmacological inhibition of soluble PRR production to unravel the precise contribution of the intrarenal RAS to renal injury induced by unilateral ureteral obstruction. We examined the impact of CD-specific deletion of PRR, CD-specific deletion of renin, and S1P (site-1 protease) inhibitor PF429242 treatment on renal fibrosis and inflammation and the indices of the intrarenal RAS in a mouse model of unilateral ureteral obstruction. After 3 days of unilateral ureteral obstruction, the indices of the intrarenal RAS including the renal medullary renin content, activity and mRNA expression, and Ang (angiotensin) II content in obstructed kidneys of floxed mice were all increased. That effect was reversed with CD-specific deletion of PRR, CD-specific deletion of renin, and PF429242 treatment, accompanied by consistent improvement in renal fibrosis and inflammation. On the other hand, renal cortical renin levels were unaffected by unilateral ureteral obstruction, irrespective of the genotype. Similar results were obtained via pharmacological inhibition of S1P, the key protease for the generation of soluble PRR. Our results reveal that PRR-dependent/soluble PRR-dependent activation of CD renin represents a key determinant of the intrarenal RAS and, thus, obstruction-induced renal inflammation and fibrosis.

Involvement of Protein-Tyrosine Phosphatase ζ Receptor on the Progression of Kidney Fibrosis in Mice with Unilateral Ureteral Obstruction

Involvement of Protein-Tyrosine Phosphatase ζ Receptor on the Progression of Kidney Fibrosis in Mice with Unilateral Ureteral Obstruction

Isorhamnetin Alleviates Renal Fibrosis by Inducing Endogenous Hydrogen Sulfide and Regulating Thiol-Based Redox State in Obstructed Kidneys.

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H2S), we speculated that ISO may work through the induction of endogenous H2S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial-mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H2S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H2S production in vivo and in vitro. The elevated H2S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H2S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H2S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H2S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H2S, the H2S-inducing nature of ISO could be exploited to treat various diseases.

Intelligent Ureteral Stent Placeable via Standard Procedure for Kidney Pressure Telemetry: An Ex-Vivo Study.

This paper reports the first telemetric ureteral stent compatible with common placement procedure, enabling wireless sensing and detection of ureteral obstruction and resultant kidney swelling known as hydronephrosis at an early stage. This sensor-integrated "intelligent" ureteral stent is prototyped via the design and fabrication approaches that raise the practicality of the device and tested in a harvested swine kidney-ureter model ex vivo. Leveraging a polymeric double-J stent and micro-electro-mechanical systems technology, the intelligent stent is built by embedding micro pressure sensors and a radiofrequency antenna, forming a resonant circuit that enables wireless kidney pressure monitoring in an operating frequency of 40-50MHz. The stent device is entirely packaged with Parylene-C for both biocompatibility and electrical insulation of the device in order to function in the real environment including urine, an electrically conductive liquid. A comparison between the results measured in in-vitro and ex-vivo settings show a good match in the sensitivity to applied pressure. In particular, the ex-vivo test in the kidney-ureter model pressurized with artificial urine in a cycled manner demonstrates wireless pressure tracking with a response of 1.3kHz/mmHg, over pressures up to 37mmHg that well covers a range of pressure increase known for chronic obstruction. This testing is enabled by the prototype placement into the ex-vivo model using the standard stenting technique and tools without noticeable functional degradation or failures, showing potential compatibility of the device with today's clinical need as a ureteral stent.

A Systematic Review of Ureteral Reimplantation Techniques in Endometriosis: Laparoscopic Versus Robotic-Assisted Approach.

Introduction: Endometriosis, characterized by the presence of endometrial tissue outside the uterus, includes deep endometriosis (DE), which can affect the urinary tract. Ureteral endometriosis (UE) is a rare but significant manifestation that can lead to ureteral obstruction, hydronephrosis, and potential kidney loss. This systematic review evaluates the effectiveness and outcomes of laparoscopic versus robotic-assisted ureteral reimplantation techniques in patients with UE. Materials and Methods: A systematic literature search was conducted following PRISMA guidelines across PubMed, MEDLINE, Embase, Web of Science, and the Cochrane Library, from inception to July 2024. Studies included patients with UE who underwent ureteral reimplantation using laparoscopic or robotic-assisted techniques. Data on patient demographics, surgical technique, duration of surgery, complications, follow-up duration, and clinical outcomes were extracted and analyzed. Results: Twelve studies met the inclusion criteria, comprising 225 patients in the laparoscopic group and 24 in the robotic-assisted group. Lich-Gregoir ureteral reimplantation, with or without a psoas hitch, was the predominant technique used. The average surgery duration was 271.1 min for the laparoscopic group and 310.4 min for the robotic-assisted group. Recurrence rates for UE were 2.95% for laparoscopic and 5.9% for robotic-assisted procedures. The robotic-assisted group had a significantly shorter hospital stay (6.7 days vs. 9.1 days, p < 0.01). Postoperative complication rates were comparable between the two techniques (p = 0.422). Conclusions: Both laparoscopic and robotic-assisted techniques for ureteral reimplantation in UE are safe and effective, with the choice of technique guided by surgeon expertise and specific clinical scenarios. However, the limited number of robotic cases introduces a bias, despite statistical significance.

Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13a with the respective IC50 of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 μg·h/L. Oral administration of 13a (0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.

Trim21 mediates metabolic reprogramming in renal tubular cells via PFKP ubiquitination to alleviate renal fibrosis

AbstractChronic kidney disease (CKD), stemming from varied nephric impairments, manifests a steadily escalating global incidence. As a progressive pathological condition, CKD is typified by an intensification in the gravity of renal interstitium fibrotic transformations. Nonetheless, the intrinsic mechanisms underpinning nephric fibrosis remain elusive. In this context, we elucidated a marked augmentation in aerobic glycolysis within proximal tubular epithelial cells (TECs) of CKD patients, alongside unilateral ureteral obstruction (UUO) and ischemia‐reperfusion injury (IRI) murine models, concomitant with deficiency of Trim21. Experimental investigations, both in vivo and in vitro, revealed that Trim21 deficiency aggravates the aberrantly heightened aerobic glycolysis, thereby exacerbating fibrotic reaction progression. Concomitantly, enhancive glycolytic flux paralleled an elevation in ATP genesis and reconstitution of cytoskeletal architecture. Mechanistically, we uncovered that Trim21 modulates aerobic glycolysis in TECs via ubiquitin‐facilitated degradation of phosphofructokinase platelet (PFKP), thus attenuating nephric fibrosis. Collectively, our insights posit Trim21 as a prospective therapeutic target in the amelioration of renal fibrosis.

Long-term outcomes of Allium ureteral stent as a treatment for ureteral obstruction

Ureteral obstruction is a prevalent urological condition associated with significant complications. The purpose of our study was to assess the safety and efficacy of a novel self-expanding, large caliber, biocompatible polymer-coated ureteral stent (Allium) for the treatment of ureteral obstructions. We conducted a retrospective analysis of data from patients who underwent Allium ureteral stent placement at our institute between November 2018 and May 2023. Demographic, clinical, and perioperative parameters were collected and analyzed. Logistic regression analyses were performed to identify preoperative factors predicting Allium stent migration. The study cohort comprised 30 patients who received a total of 40 successfully implanted Allium stents. No significant adverse events related to the insertion procedure were observed. During a median follow-up period of 29 months (range: 1–60 months), migration occurred in 11 (27.5%) stents while encrustation was noted in 8 (20%) stents. The median functional duration of the Allium stents was found to be 22 months (range:1–60 months), with an overall functioning rate at last follow-up being recorded as 59.5%. Multivariate analysis revealed that the glomerular filtration rate of the ipsilateral kidney was the sole risk factor predictive of Allium stent migration. With its minimal invasiveness and good tolerability, the Allium stent represents a safe and viable management option for treating ureteric obstructions; however, it should not be considered as definitive treatment but rather as an alternative option for patients unwilling or unsuitable for definitive treatment, particularly high-risk individuals or elderly patients exhibiting decreased ipsilateral glomerular filtration rates.

The JNK-associated leucine zipper protein exerts a protective effect on renal parenchymal injury by limiting the inflammatory secretome in tubular cells

JNK-associated leucine zipper protein (JLP) is a newly identified renal endogenous anti-fibrotic factor that is selectively enriched in renal tubular epithelial cells (TECs). The loss of JLP by TECs is a landmark event that heralds the progression of kidney fibrosis. JLP deficiency ensues a series of pathogenetic cellular processes that are conducive to fibrotic injury. Inflammatory injury is functionally relevant in fibrotic kidneys, and TECs play an essential role in fueling inflammation through aberrant secretions. It is speculated that the loss of JLP in TECs is associated with the relentless inflammation during the development of kidney fibrosis. This study examined the alteration of a panel of inflammatory signatures in TECs under kidney fibrotic circumstances using a Jlp gene-modified unilateral ureteral obstruction (UUO) mouse model or cultured HK-2 cells. It was found that a deficiency of JLP in TECs led to a significant increase in the secretion of inflammatory cytokines including interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and monocyte chemotactic protein-1 (MCP-1), overactivation of the nuclear factor (NF)-κB/c-Jun N-terminal kinase (JNK) pathway, as well as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis in response to pro-fibrotic damage. Additionally, the absence of JLP resulted in enhanced macrophage migration and fibroblast activation as paracrine effects elicited by injured TECs. In conclusion, the loss of JLP in TECs catalyses inflammatory injuries in the development of kidney fibrosis.

Comparative Feasibility Analysis of Retrograde Double J Stenting, Antegrade Double J Stenting, and Percutaneous Nephrostomy Tube Placement for Ureteric Obstruction Secondary to Pelvic Malignancies

Background: The management of ureteric obstruction secondary to pelvic malignancies (UOPM) presents a significant challenge. Objectives: Our study aimed to assess the factors affecting the feasibility of interventions for patients with UOPM - including retrograde and antegrade double J (DJ) stenting, and percutaneous nephrostomy (PCN) insertion. Methods: We conducted a retrospective analysis of patients who underwent intervention for UOPM over two years, from January 2022 to December 2023. Patients were categorized into groups based on intervention type: Group 1: Retrograde DJ stenting, group 2: Antegrade DJ stenting, and group 3: PCN insertion. Demographic, clinical, radiological, cystoscopic, and laboratory data were compared between the three groups. Analysis of Variance (ANOVA), logistic regression, and marginal mean plots were utilized for statistical analysis. Results: Fifty–nine patients were included in the study, consisting of 14 males and 45 females, and the mean age of the study population was 60.1 ± 10.8 years. Retrograde DJ stenting was successfully achieved in 59.3% of patients, with 10.2% undergoing antegrade DJ stenting and 30.5% needing PCN insertion. Serum albumin (P = 0.04), serum creatinine (P = 0.02), albumin creatinine ratio (P &lt; 0.001), and severity of hydroureteronephrosis (HDUN) (P = 0.02) were significantly associated with intervention outcomes. There was an increased likelihood of PCN insertion in higher serum creatinine and lower serum albumin levels. Multinomial logistic regression with univariate and multivariate analysis revealed significance among the above-mentioned variables. Conclusions: Even though DJ stenting remains common, a significant proportion of patients require PCN insertion. Serum albumin, serum creatinine, albumin creatinine ratio, and HDUN severity are significant predictors of intervention success. Further research is warranted to validate these findings and enhance management strategies for UOPM.