Miguel Hueso

Circular RNAs (circRNAs) are covalently closed RNA molecules generated through backsplicing of precursor messenger RNA (mRNA) transcripts. Although circRNAs lack the 5′ cap and the 3′ poly(A) tail characteristic of linear mRNAs, their circular structure confers enhanced stability and resistance to exonucleolytic degradation, establishing circRNAs as important regulators of gene expression that contribute to cellular homeostasis and disease progression. circRNAs regulate gene expression at multiple levels through microRNA sequestration, modulation of RNA-binding protein activity, regulation of transcription and splicing, and even translation into functional micropeptides, with emerging evidence supporting their involvement in the splicing machinery. Here, we will review current knowledge on circRNA biogenesis and function, mainly focusing on their impact on the transition from inflammation to tissue repair, fibrotic remodeling, and disease progression. Special attention is devoted to circRNA-mediated regulatory networks in renal disease, while placing these findings within the broader context of fibrotic and inflammatory disorders affecting multiple organs. We further examine the potential of circRNAs as stable, tissue-specific biomarkers and therapeutic targets, while highlighting the emerging use of endogenous and engineered circRNAs as platforms for RNA-based therapeutics and vaccines. By integrating mechanistic insights with functional and translational perspectives, this review provides a framework for understanding circRNAs as active components of RNA regulatory networks and outline the key challenges and opportunities for their future clinical translation.

Microplastics (MPs) and nanoplastics (NPs) are emerging environmental contaminants with increasing evidence of human exposure and potential adverse health effects. The kidney, due to its central role in filtration and excretion, represents a plausible target for MPs and NPs accumulation and toxicity. Experimental studies show that MPs and NPs can accumulate in renal tissue, inducing oxidative stress, inflammation, mitochondrial dysfunction, autophagy, pyroptosis and apoptosis, along with histopathological changes such as tubular injury and early fibrosis. In addition to direct effects, MPs may contribute to renal damage through systemic pathways, including the gut–kidney axis and the transport of associated toxic chemicals. Patients with chronic kidney disease (CKD) and those undergoing dialysis may be particularly vulnerable due to impaired clearance and potential additional exposure from medical materials and fluids. In hemodialysis, this includes repeated contact with polymer-based tubing and membranes and the use of large volumes of treated water, whereas in peritoneal dialysis it may arise from polymeric bags and solutions that are stored and heated prior to administration. However, human data remains limited, and most evidence is derived from high-dose experimental models. The high physicochemical diversity of MPs and NPs further complicates hazard identification and risk assessment, highlighting the need for simplified toxicity-based classification frameworks. This narrative review summarizes current knowledge on sources, composition, detection methods, and renal effects of MPs and NPs, and identifies key gaps in exposure assessment, mechanistic understanding, and clinical translation. Addressing these limitations is essential to clarify their role in kidney disease and to inform risk assessment, regulatory strategies, and mitigation measures.

Background: There is a need for improved disease-targeting therapies for autosomal dominant polycystic kidney disease (ADPKD). This study evaluated the efficacy and safety of GLPG2737, a cystic fibrosis transmembrane conductance regulator inhibitor, in ADPKD. Methods: MANGROVE (NCT04578548) was an exploratory, phase 2a, proof-of-concept, randomized, multicentre study. Eligible patients were aged 18–50 years with rapidly progressing, typical ADPKD. Patients were randomly assigned (2:1) to double-blind treatment with once-daily, oral GLPG2737 150 mg or placebo for 52 weeks. This was followed by a 52-week open-label extension (OLE) period, in which all patients received GLPG2737. Both periods had a 4-week follow-up period without treatment. Primary endpoints were the mean percentage change from baseline in height-adjusted total kidney volume (htTKV), and frequency and severity of treatment-emergent adverse events (TEAEs). A key secondary endpoint was the mean change from baseline in estimated glomerular filtration rate (eGFR). Results: Overall, 89 patients were screened between 10 November 2020 and 2 March 2023; 66 patients received treatment (GLPG2737, n = 44; placebo, n = 22), and 61 patients completed the double-blind period (GLPG2737, 41/44; placebo, 20/22). Changes in htTKV from baseline to week 52 did not differ between GLPG2737 and placebo (GLPG2737: 8.2% [95% confidence interval (CI) 6.0%, 10.4%]; placebo: 9.2% [95% CI 6.1%, 12.4%]; between-treatment difference: −0.91% [95% CI: −4.34%, 2.64%], P = 0.61). There were no life-threatening TEAEs or deaths. Similar proportions of patients had treatment-related TEAEs in the GLPG2737 (13/44, 30%) and placebo (6/22, 27%) groups. Mean between-treatment difference for change in eGFR from baseline to week 52 (GLPG2737 vs placebo) was not significant − 2.31 mL/min/1.73 m2 (95% CI − 5.64, 1.02; P = 0.17). Conclusions: Overall, GLPG2737 was generally well tolerated. However, GLPG2737 150 mg once daily was not efficacious in reducing htTKV or slowing eGFR decline over 52 weeks compared with placebo. Thus, the study was terminated early after the double-blind period; results from the OLE period are reported in brief.

Our study investigates the role of inflammation and monocyte trafficking in atherosclerosis (ATH). We show that miR-125b-5p increases plaque inflammation and downregulates CCR7. Targeting miR-125b-5p with a specific antagomir restores CCR7 expression, enhances macrophage migration, and reduces both the inflammation and plaque size. The miR-125b-5p/CCR7 axis in ATH progression was further validated in a cohort of patients, suggesting that modulating this pathway may offer a novel therapeutic strategy.

Background and Aims: Elevated homocysteine (Hcy) levels are a risk factor for cardiovascular diseases, including atherosclerosis. MicroRNAs (miRNAs) influence genes linked to atherosclerosis, but their role in hyperhomocysteinemia (HHcy) remains unclear. miR-30d-5p is up-regulated in the plasma of patients with HHcy and deep venous thrombosis (DVT), with TIMP3 identified as a potential target. In this study, we aimed to investigate whether HHcy-induced miR-30d-5p regulates TIMP3 and its downstream effects on metalloproteinases MMP2 and MMP9, thereby playing a role in the pathophysiology of atherosclerosis. Methods: Mouse and human macrophages were treated with Hcy to assess gene and protein expression. Transfection experiments and dual luciferase reporter assays confirmed miRNA-target interactions. ApoE-/- mice received Hcy supplementation (1.8 g/L DL-Hcy) to induce atherosclerosis, with analyses of lesions, CD68, TIMP3 immunostaining, and in situ metalloproteinase activity. Results: miR-30d-5p was up-regulated in macrophages treated with Hcy, while TIMP3 expression decreased. TIMP3 was validated as a direct miR-30d-5p target through luciferase assays. miR-30d-5p inhibition in macrophages restored TIMP3 expression, whereas miR-30d-5p overexpression increased MMP9 and MMP2 protein levels and activity. In vivo, HHcy-induced atherosclerosis in ApoE-/- mice showed larger aortic lesions, higher macrophage and miR-30d-5p content, reduced TIMP3 levels, and elevated metalloproteinase activity compared to controls. Conclusions: These results provide evidence that miR-30d-5p downregulates TIMP3 and increases the activity of MMP9 in vitro and in vivo, suggesting another potential mechanism by which Hcy affects atherogenicity.

Background. Variant 3′UTRs provide mRNAs with different binding sites for miRNAs or RNA-binding proteins (RBPs) allowing the establishment of new regulatory environments. Regulation of 3′UTR length impacts on the control of gene expression by regulating accessibility of miRNAs or RBPs to homologous sequences in mRNAs. Objective. Studying the dynamics of mRNA length variations in atherosclerosis (ATS) progression and reversion in ApoE-deficient mice exposed to a high-fat diet and treated with an αCD40-specific siRNA or with a sequence-scrambled siRNA as control. Methods. We gathered microarray mRNA expression data from the aortas of mice after 2 or 16 weeks of treatments, and used these data in a Bioinformatics analysis. Results. Here, we report the lengthening of the 5′UTR/3′UTRs and the shortening of the CDS in downregulated mRNAs during ATS progression. Furthermore, treatment with the αCD40-specific siRNA resulted in the partial reversion of the 3′UTR lengthening. Exon analysis showed that these length variations were actually due to changes in the number of exons embedded in mRNAs, and the further examination of transcripts co-expressed at weeks 2 and 16 in mice treated with the control siRNA revealed a process of mRNA isoform switching in which transcript variants differed in the patterns of alternative splicing or activated latent/cryptic splice sites. Conclusion. We document length variations in the 5′UTR/3′UTR and CDS of mRNAs downregulated during atherosclerosis progression and suggest a role for mRNA splicing reprogramming and transcript isoform switching in the generation of disease-related mRNA sequence diversity and variability.

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-known complication that increases morbidity and mortality rates. The objective of this study was to reduce CSA-AKI through nephrologist intervention in patients awaiting cardiac surgery.Methods: We performed a single center, open-label, randomized clinical trial including 380 patients who underwent scheduled cardiac surgery at the Hospital de Bellvitge between July 2015 and October 2019. A total of 184 patients were evaluated by the same Nephrologist one month before the surgery to minimize the risk factors for AKI. In addition to assessments at the outpatient clinic, we also collected clinical data during hospitalization and during the first year.Results: Despite the intervention, no differences were observed between the groups in the incidence of CSA-AKI (intervention group 26.37% vs. standard of care 25.13%, p=0.874), mortality (3.91% vs. 3.59%, p=0.999), length of Intensive Care Unit (ICU) stay (10 days [7.00;15.0] for both groups, p=0.347), or renal function after one year of follow-up (estimated glomerular filtration rate (eGFR) by CKD-EPI: 74.5 ml/min (standard deviation 20.6) vs 76.7 (20.8) ml/min, respectively, p=0.364). A reduction in the need for blood transfusion was observed in the intervention group, although the difference was not statistically significant (37.22% vs. 45.03%, p =0.155).Conclusion: In this clinical trial, nephrologist intervention in the entire population on the cardiac surgery waiting list did not show a nephroprotective benefit.Clinical trial registration: ClinicalTrials.gov, identifier (NCT02643745).

Importance: Cardiac surgery–associated acute kidney injury (CSA-AKI) remains a significant problem following cardiopulmonary bypass (CPB). Various strategies are proposed to attenuate CSA-AKI, including extracorporeal blood purification (EBP), but little is known about the effect of EBP through an acrylonitrile-sodium methallylsulfonate/polyethyleneimine membrane during CPB.Objective: To determine whether the use of an EBP device in a nonemergent cardiac surgery population reduces CSA-AKI after CPB.Design, Setting, and Participants: This double-blind, randomized clinical trial was conducted in 2 tertiary hospitals in Spain. Patients 18 years or older undergoing nonemergent cardiac surgery who were at high risk for CSA-AKI were enrolled from June 15, 2016, through November 5, 2021, with follow-up data through February 5, 2022. Of 1156 patients assessed, 343 patients were randomized (1:1) to either receive EBP or standard care.Intervention: Nonselective EBP device connected to the CPB circuit.Main Outcomes and Measures: The primary outcome was the rate of CSA-AKI in the 7 days after randomization.Results: Among 343 patients randomized (169 to receive EBP and 174 to receive usual care), the mean (SD) age was 69 (9) years and 119 were females. The rate of CSA-AKI was 28.4% (95% CI, 21.7%-35.8%) in the EBP group vs 39.7% (95% CI, 32.3%-47.3%) in the standard care group (P = .03), with an adjusted difference of 10.4% (95% CI, 2.3%-18.5%) using a log-binomial model (P = .01). No significant differences (P > .05) were observed in most of the predefined clinical secondary end points or post hoc exploratory end points. In a sensitivity analysis, EBP was found to be more effective in terms of CSA-AKI reduction in patients with chronic kidney disease, diabetes, hypertension, low left ventricular ejection fraction (<40%), and lower body mass index (<30). No differences were observed between the groups in adverse events tracking.Conclusions and Relevance: The use of a nonselective EBP device connected to the CPB circuit in a nonemergent population of patients undergoing cardiac surgery was associated with a significant reduction of CSA-AKI in the first 7 days after surgery.Trial Registration: ClinicalTrials.gov Identifier: NCT02518087