ACE2 Deficiency Protects Against Heme Protein-Induced Acute Kidney InjuryCroatt, Singh, Grande
et alAm J Physiol Renal Physiol (2025)
Abstract: Angiotensin-converting enzyme 2 (ACE2) exerts countervailing effects on the renin-angiotensin aldosterone system. ACE2 also engages the spike protein of SARS-CoV-2. ACE2 protein has been shown recently to avidly bind heme. We examined the pathobiologic relevance of this heme-binding property of ACE2 by employing the glycerol-induced model of heme protein mediated AKI (HP-AKI) which is characterized by increased kidney heme content. We studied the response of ACE2-wildtype (ACE2+/y) and ACE2-deficient (ACE2-/y) mice to HP-AKI and quantitated kidney and cellular content of heme under relevant conditions. ACE2-deficient mice, compared with ACE2-wildtype mice, were significantly protected against HP-AKI as reflected by filtration markers, less histologic injury, and less expression of apoptosis and ferroptosis markers. ACE2-deficient mice also evinced lesser kidney heme content and a blunted induction of HO-1. HEK293 ACE2-overexpressing cells, compared with HEK293-native, when exposed to heme, retained higher amounts of heme. In HP-AKI, ACE2 expression and activity were reduced, and myoglobin and heme, administered independently, reduced ACE2 expression in the otherwise intact mouse kidney. Finally, with more severe HP-AKI, the protective effect of ACE2 deficiency was attenuated. We conclude that ACE2 deficiency confers protection against HP-AKI. We suggest that this reflects the recently recognized binding of heme to ACE2, such binding serving to facilitate renal entry of heme, a known nephrotoxin. These findings uncover a novel pathway of heme-dependent acute kidney injury. This is the first demonstration of the biologic relevance of chemical binding of heme by ACE2. Finally, we identify heme proteins and heme as novel determinants of ACE2 expression.
Modulation of RAAS receptors and miRNAs in COVID-19: implications for disease severity, immune response, and potential therapeutic targetsBarreto Fernandes, Pilotto, Cezar
et alBMC Infect Dis (2025) 25 (1), 399
Abstract: The SARS-CoV-2 spike protein interacts with ACE2, a key receptor within the renin-angiotensin-aldosterone system (RAAS), which plays a critical role in maintaining vascular homeostasis, regulating blood pressure, and modulating inflammation. An observational study analyzed the gene expression profiles of RAAS receptors and associated miRNAs in 88 hospitalized COVID-19 patients and 20 healthy controls, comparing the acute and post-acute phases to assess their impact on disease severity and recovery. Our findings revealed an association between reduced MAS1 expression in both advanced age (P = 0.03) and the need for oxygen supplementation (P = 0.04). Additionally, reduced ACE expression was associated with worse mortality outcomes (P = 0.01). Notably, ACE2 and TMPRSS2 expression was significantly decreased (P < 0.0001) in individuals requiring oxygen supplementation and in those with diabetes mellitus during both the acute and post-COVID-19 phases, further highlighting the impact of these conditions on RAAS. The miRNA analysis revealed significant downregulation of miR-200c (P = 0.005), miR-let-7 (P = 0.01), and miR-122 (P = 0.03) in acute-phase COVID-19 patients. This dysregulation contributes to the inflammatory response and highlights the interaction between viral entry and immune regulation. These results underscore the significance of the ACE2/Ang-(1-7)/MAS1 axis in inflammation regulation and suggest that targeting this pathway may have therapeutic potential. Our study provides valuable insights into the molecular mechanisms of COVID-19 pathogenesis and identifies the modulation of RAAS receptors and miRNAs as promising biomarkers for disease severity and potential therapeutic interventions. CLINICAL TRIAL: Not applicable.© 2025. The Author(s).
Diagnostic Value of Let-7a-5p in Essential HypertensionWang, Zhu, Cheng
et alJ Clin Hypertens (Greenwich) (2025) 27 (3), e70033
Abstract: This study aimed to investigate the role of let-7a-5p in the pathogenesis of essential hypertension (EH) and its correlation with the renin-angiotensin-aldosterone system (RAAS) biomarkers. Ninety-eight EH patients and 24 healthy controls (HC) enrolled in the study were assayed for the relative expression of let-7a-5p in plasma by quantitative real-time polymerase chain reaction (Q-PCR), and biomarkers of the RAAS system, including angiotensin-converting enzyme 2 (ACE2), Ang (1-7), MAS1, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R), were determined by enzyme-linked immunosorbent assay (ELISA) The expression levels of the biomarkers of RAAS system were determined. The results showed that the expression levels of let-7a-5p in the plasma of EH patients were remarkably higher than those of HC. The prediction model of combined let-7a-5p showed high accuracy by constructing a subject operating characteristic (ROC) curve with an area under the curve (AUC) of 0.885, and the reliability of the model was further verified by the Hosmer-Lemeshow (H-L) goodness-of-fit test, the Model Calibration Curve, and the Decision Curve Analysis. Spearman correlation analysis revealed that the expression of let-7a-5p was positively correlated with ACE (r = 0.352, p < 0.001), and mediation analysis indicated that ACE partially mediated between let-7a-5p and the development of hypertension. The present study concludes with the potential of let-7a-5p as a companion diagnostic biomarker for EH. It suggests that there may be a complex regulatory mechanism between it and specific RAAS biomarkers, which provides a new perspective on the pathogenesis and diagnosis of EH.© 2025 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.
Interaction of Asparagusic Acid, Asparaptines and Related Dithiolane Derivatives With Angiotensin-Converting Enzyme-2 (ACE-2): A Molecular Docking StudyVergoten, Bailly
J Biochem Mol Toxicol (2025) 39 (4), e70236
Abstract: A variety of sulfur-containing small molecules can be found in the spears of asparagus (Asparagus Officinalis L.) including compounds derived from asparagusic acid such as the amino acid derivatives asparaptines A, B, and C. The previous characterization of asparaptine A as an inhibitor of angiotensin-converting enzyme (ACE) prompted us to compare the binding of the three asparaptines to ACE2 using molecular modeling. The lysine conjugate asparaptine B was found to bind better to the enzyme than the arginine (asparaptine A) and histidine (asparaptine C) conjugates. The stability of ACE2-asparaptine B complexes was only a little inferior to that observed with the reference ACE2 inhibitor MLN-4760. On this basis, 20 additional compounds bearing a thiol group or a dithiolane motif were evaluated as potential binders to ACE2 using the same docking methodology. Three compounds emerged as robust ACE2 binders: the natural products isovalthine and N-acetyl-felinine, and the drug candidate CMX-2043. The empirical energy of interaction (ΔE) of N-acetyl-felinine with ACE2 was comparable to that measured with asparaptine B, and a little higher with the thiol metabolite isovalthine. Remarkably, CMX-2043 revealed a high capacity to form stable complexes with ACE2, superior to that of the reference MLN-4760. Both the l-Glu-l-Ala dipeptide motif and the α-lipoic acid moiety of CMX-2043 are implicated in the protein interaction. Our observations pave the way to the design of novel ligands of ACE2 equipped with a dithiolane motif.© 2025 The Author(s). Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.
膜杰作
Star Staining
