Angiotensin-converting enzyme (ACE), primarily expressed in vascular endothelial and renal tubular epithelial cells, regulates vascular tone and contributes to kidney injury, including in diabetic kidney disease (DKD). While tubular ACE deletion ameliorates tubulointerstitial injury in diabetic mice, the role of ACE in macrophages remains unclear. We investigated diabetic ACE 10/10 mice, which overexpress ACE exclusively in myelomonocytic cells and lack ACE in other tissues, including the kidney. In diabetic ACE 10/10 mice, the absence of endothelial ACE resulted in the elimination of glomerular hyperfiltration with preservation of podocyte structure. However, albuminuria levels remained comparable to those in diabetic WT mice. Furthermore, despite the lack of tubular ACE, which is recognized as a contributor to tubulointerstitial fibrosis, the extent of fibrosis was similarly unchanged. Flow cytometry revealed that ACE expression in kidney-resident macrophages increased approximately threefold in both diabetic WT and ACE 10/10 mice, but not in peritoneal macrophages. In vitro, ACE-overexpressing macrophages showed increased interleukin-6 production and enhanced chemotaxis upon lipopolysaccharide stimulation. These findings suggest that ACE expressed in kidney-resident macrophages contributes to proximal tubular albuminuria and tubulointerstitial fibrosis in DKD, independently of glomerular hyperfiltration and tubular ACE. Although macrophage ACE represents a minor fraction of total renal ACE, it may serve as a novel therapeutic target.

KRAS G12C mutations occur in approximately 11

The potential of the immune system to decrease cancer progression is widely recognized and has led to the development of innovative anti-cancer immunotherapies. Here, we studied human macrophages derived from genetically engineered iPSCs (iMac) with angiotensin-converting enzyme (ACE) expression regulatable by a doxycycline (dox)-inducible promoter as a novel anti-cancer immunotherapy. Increased ACE expression in iMac (cells now termed ACE-iMac) augments polarization towards an M1 macrophage phenotype characterized by increased production of proinflammatory cytokines, reactive oxygen species, nitric oxide, and an RNA profile indicating an aggressive immune response. ACE-iMac kills tumor cells in vitro significantly better than iMac. In vivo, studies using tumor xenografts for melanoma, breast cancer, and head and neck squamous cell carcinoma (HNSCC) showed a highly significant 3.4- to 7.2-fold reduction in solid tumor size following ACE-expressing ACE-iMac immunotherapy as compared to results with iMac. To further investigate the impact of ACE on human anti-tumor responses, we developed a humanized BLT-NSG mouse model with a fully functional adaptive immune system. Here, ACE-iMac treatment significantly reduced the growth of human melanoma xenografts by enhancing the activation of human T cells and NK cells. In conclusion, enhancing ACE expression in human-derived macrophages (ACE-iMac) greatly amplifies their anti-cancer phenotype, offering a compelling new therapeutic strategy with the potential to improve clinical outcomes for cancer patients.

Angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase, is known to cleave amyloid-beta (Aβ), and its reduced activity has been linked to the progression of Alzheimer’s disease (AD). Our research indicates that ACE is vital for myeloid cell functions. Using ACE10/10 recombinant mice, we demonstrated that overexpressing ACE in macrophages mitigates AD pathology in these mice. Given that neutrophils are the most abundant white blood cells, this study investigates whether ACE overexpression in neutrophils influences AD progression. We crossed NeuACE mice, which overexpress ACE in neutrophils, with 3xTg-AD mice to create AD-NeuACE mice. Behavioral changes and brain pathology were assessed through various behavioral mazes and histological assays. AD-NeuACE mice demonstrated improved cognitive functions and lower Aβ levels in the cortex and hippocampus compared to AD mice. In-vitro data indicate that ACE-overexpressing neutrophils are significantly more effective at phagocytosing and clearing Aβ fluorescence particles. This study suggests that overexpressing ACE in neutrophils could be a promising approach to managing AD-like phenotypes.

Angiotensin-converting enzymes (ACE and ACE2) are key components of the renin-angiotensin-aldosterone system (RAAS) and are present in the gastrointestinal tract and intestinal content, preserving their catalytic activity, and may interact with the gut microbiota. The present study aimed to determine the origin of fecal ACE and ACE2 activity. Fecal pellets from germ-free, ACE and ACE2 knockout (KO) mice, and from the corresponding controls were analyzed using fluorimetric enzyme activity assays. ACE activity was assessed using Hippuryl-His-Leu and Z-Phe-His-Leu as substrates; ACE2 activity was assessed using Mca-APK (Dnp), with and without the ACE2 inhibitor MLN-4760. Germ-free mice showed increased fecal ACE and ACE2 activity compared to controls. ACE2-KO mice lacked fecal ACE2 activity, whereas ACE activity was unaffected. In ACE-KO mice, fecal ACE activity was reduced, but not abolished, while ACE2 activity remained similar to controls. In ACE C- and N-domain KO mice, ACE activity was similar to controls, and inhibition with captopril completely abolished fecal ACE activity using Hippuryl-His-Leu, but not Z-Phe-His-Leu, in those animals. These findings indicate that fecal ACE and ACE2 activity results from combined intestinal shedding and microbiota-related mechanisms, supporting a modulatory role of the gut environment on luminal RAAS activity.

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. The "sartan" family drugs such as losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers.

Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer’s disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD. ACE-expressing MG surround plaques more frequently and they have increased Aβ phagocytosis, endolysosomal trafficking and spleen tyrosine kinase activation downstream of the major Aβ receptors, triggering receptor expressed on myeloid cells 2 (Trem2) and C-type lectin domain family 7 member A (Clec7a). These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD. Gomez et al. show that boosting angiotensin-converting enzyme expression in microglia promotes phagocytic clearance of Aβ and endolysosomal trafficking, driven by spleen tyrosine kinase signaling in the 5xFAD transgenic model of Alzheimer’s disease.

Stereotactic radiosurgery (SRS) is used to treat residual and recurrent nonfunctioning pituitary adenomas (NFPA). Hypopituitarism is the most common complication with increasing rates over time. We present the largest multicentric cohort evaluating outcomes after radiosurgery for NFPA. Twelve centers contributed retrospective data on 869 patients treated with SRS between 1992 and 2022. Tumor progression was defined as a volumetric increase of =20% from baseline. New-onset hypopituitarism was defined as dysfunction of at least 1 pituitary axis. Kaplan–Meier curves were plotted for the probability of tumor control and new onset hypopituitarism. Cox regression was used to assess predictive factors for tumor control and new pituitary hormone deficiency. A total of 869 patients (median age 52.5 years [Interquartile range (IQR):18.9]) were treated using a median margin dose of 14Gy (IQR:4) for a median tumor volume of 3.4cc (IQR:4.3). With a median radiological follow-up of 3.7 years (IQR:4.8). Volumetric tumor reduction occurred in 451 patients (51.9%), stability in 364 (41.9%) and 54 patients (6.2%) showed tumor progression. The probability of tumor control was 95.5% (95% Confidence Interval [CI]:93.8–97.3) and 88.8% (95%CI:85.2–92.5) at 5 and 10 years. A margin dose >14 Gy was associated with tumor control (Hazard Ratio [HR]:0.33, 95% CI:0.18–0.60, P<0.001). The probability of new hypopituitarism was 9.9% (95%CI:7.3–12.5) and 15.3% (95%CI:11–19.4) at 5 and 10 years. A maximum point dose >10 Gy in the pituitary stalk was associated with new pituitary hormone deficiency (HR:3.47, 95%CI:1.95–6.19). The 10-year cumulative probability of new cortisol, thyroid, gonadotroph, and growth hormone deficiency was 8%, 8.3%, 3.5%, and 4.7%, respectively. SRS for NFPA affords long-term tumor control (10 year:>88%) and low rates of pituitary dysfunction (10-year:15.3%).

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point-in-time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70230. The Concise Guides provide expert-curated recommendations of 'Gold Standard' selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid-2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensin II. We recently reported that ACE-overexpressing neutrophils have the renoprotective role in IC-mediated crescentic GN by the complement C3b-complement receptor1/2 axis. Here, we further investigate the precise mechanism of the adverse, pathogenic, and renoprotective functions of neutrophils in GN. Nephrotoxic serum nephritis (NTN) was induced in the mice with four different conditions and analyzed: 1) neutrophil depletion in wild-type (WT) and NeuACE mice that overexpress ACE specifically in neutrophils; 2) adoptive transfer of ACE-overexpressing neutrophils into WT mice; 3) analysis of ACE's catalytic C and N domains using each domain-knockout (Tg-CKO and Tg-NKO) and WT-ACE transgenic (Tg-ACE) mice; and 4) comparison between C3KO and C3KO-NeuACE mice that overexpress ACE in neutrophils but lack of complement C3. The results were as follows: 1) WT mice without neutrophils showed ameliorated glomerular injury, whereas neutrophil-depleted NeuACE mice lost the renoprotective effect; 2) WT mice with ACE-overexpressing neutrophils exhibited less severe glomerular injury; 3) Tg-CKO or Tg-NKO mice showed a partial loss of the renoprotective effects compared with Tg-ACE mice, suggesting both C and N domains are needed for full renoprotection; and 4) C3KO-NeuACE mice lost the renoprotective effects. Complement C3 is essential for the renoprotection of overexpressed neutrophilic ACE in NeuACE mice. The present study demonstrated that canonical pathogenic effects of neutrophils were overcome by the noncanonical renoprotection by neutrophils through both C and N domains of ACE and complement C3.NEW & NOTEWORTHY We recently reported that NeuACE mice that overexpress angiotensin-converting enzyme (ACE), specifically in neutrophils, alleviate glomerular injury in immune complex-mediated crescentic glomerulonephritis by the complement C3b-complement receptor 1/2 axis. Here, we showed that catalytically active C and N domains of ACE were needed for full renoprotection, and complement C3 was essential for the renoprotective role of overexpressed neutrophilic ACE. Furthermore, we highlighted the neutrophils' canonical pathogenic and noncanonical renoprotective functions via neutrophilic ACE through complement C3 in glomerulonephritis.

An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.

Natural opioid signals in the brain produced by Met-enkephalin-Arg-Phe are enhanced after blocking its degradation by the N-terminal catalytic domain of angiotensin-converting enzyme.

Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95

BACKGROUND AND OBJECTIVES: The management of World Health Organization (WHO) grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited but suggests that a higher dose is better for tumor control. We characterize the predictors of post-SRS outcomes that can help guide planning and management. METHODS: We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. RESULTS: Ninety-nine patients (median age 62 years) underwent SRS, 11 of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received previous irradiation. The median follow-up was 49 months. The median overall survival was 119 months (95% CI 92-NA) with estimated 5- and 10-year survival of 83% and 27%, respectively. The median progression-free survival (PFS) was 40 months (95% CI 32-62), with 3- and 5-year rates at 54% and 35%, respectively. The median locomarginal PFS was 63 months (95% CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 Common Terminology Criteria for Adverse Events grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session cohort, Ki-67 significantly predicted both overall survival and intracranial PFS. Tumors with Ki-67 >10% had 2.17 times the risk of locomarginal progression compared with Ki-67 ≤10% (P = .018) adjusting for covariates. Sex, prescription dose, tumor volume, and location also predicted tumor control. In tumors with Ki-67 >10%, margin dose ≥14 Gy was associated with significantly better tumor control but not for tumors with Ki-67 ≤10%. CONCLUSION: The management of WHO grade 2 meningiomas requires a multimodality approach. This study demonstrates the value of a targeted SRS approach in patients with limited disease and further establishes predictive biomarkers that can guide planning through a personalized approach.

The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

Genome-wide association studies (GWAS) have identified many gene polymorphisms associated with an increased risk of developing Late Onset Alzheimer's Disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing microglia innate immune responses and lipid metabolism. Angiotensin Converting Enzyme (ACE), a GWAS LOAD risk-associated gene best known for its role in regulating systemic blood pressure, also enhances innate immunity and lipid processing in peripheral myeloid cells, but a role for ACE in modulating the function of myeloid-derived microglia remains unexplored. Using novel mice engineered to express ACE in microglia and CNS associated macrophages (CAMs), we find that ACE expression in microglia reduces Aβ plaque load, preserves vulnerable neurons and excitatory synapses, and greatly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of Alzheimer's Disease (AD). ACE-expressing microglia show enhanced Aβ phagocytosis and endolysosomal trafficking, increased clustering around amyloid plaques, and increased SYK tyrosine kinase activation downstream of the major Aβ receptors, TREM2 and CLEC7A. Single microglia sequencing and digital spatial profiling identifies downstream SYK signaling modules that are expressed by ACE expression in microglia that mediate endolysosomal biogenesis and trafficking, mTOR and PI3K/AKT signaling, and increased oxidative phosphorylation, while gene silencing or pharmacologic inhibition of SYK activity in ACE-expressing microglia abrogates the potentiated Aβ engulfment and endolysosomal trafficking. These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing microglia as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, alpha-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPAR gamma) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPAR gamma might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPAR gamma inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These fi ndings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.