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Kidney International Feb 2024Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested...
Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.
Topics: Humans; Amides; Atypical Hemolytic Uremic Syndrome; Complement Activation; Complement C3; Complement C3-C5 Convertases; Complement Pathway, Alternative; Fumarates; Kidney Diseases; Renin
PubMed: 38008161
DOI: 10.1016/j.kint.2023.11.005 -
Revista Da Associacao Medica Brasileira... 2023The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between...
OBJECTIVE
The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between serum angiotensinogen and urinary angiotensinogen levels and the prognosis of renal function in patients diagnosed with acute kidney injury.
METHODS
A total of 79 newly diagnosed acute kidney injury patients aged 18 years and older were enrolled. Serum angiotensinogen and urinary angiotensinogen levels were measured at the onset of the disease, as well as on the 15th and 30th days of follow-up. After 3 months, renal function was evaluated by measuring serum creatinine levels.
RESULTS
Among the acute kidney injury patients, those in Kidney Disease: Improving Global Outcomes stage 3 exhibited significantly higher urinary angiotensinogen/urine creatinine levels compared with stages 1 and 2 patients at the time of diagnosis (p<0.05). Furthermore, a positive correlation was observed between the urinary angiotensinogen/urine creatinine level at the time of diagnosis and the serum creatinine level at the third month (r=0.408, p=0.048).
CONCLUSION
The findings suggest that urinary angiotensinogen levels can serve as an indicator of the severity of acute kidney injury. Monitoring urinary angiotensinogen levels could potentially contribute to the prognosis assessment and management of acute kidney injury patients.
Topics: Humans; Prognosis; Angiotensinogen; Prospective Studies; Creatinine; Biomarkers; Acute Kidney Injury; Kidney
PubMed: 37971126
DOI: 10.1590/1806-9282.20230716 -
Hypertension Research : Official... Jan 2024The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor...
Angiotensin II type 1 receptor-associated protein deletion combined with angiotensin II stimulation accelerates the development of diabetic kidney disease in mice on a C57BL/6 strain.
The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries. Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice. However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria, glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. In STZ-induced diabetic C57BL/6 mice that are resistant to the development of kidney injury, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD, which may be associated with intrarenal RAS overactivation.
Topics: Mice; Male; Animals; Angiotensin II; Receptor, Angiotensin, Type 1; Diabetic Nephropathies; Adaptor Proteins, Signal Transducing; Mice, Inbred C57BL; Kidney; Renin-Angiotensin System; Mice, Knockout; Diabetes Mellitus
PubMed: 37957242
DOI: 10.1038/s41440-023-01496-4 -
Scientific Reports Nov 2023It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen...
Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus.
It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.
Topics: Animals; Gerbillinae; Muscle, Smooth, Vascular; Angiotensinogen; Cholesterol; Hypothyroidism; Aorta; Gene Expression; Myocytes, Smooth Muscle
PubMed: 37951959
DOI: 10.1038/s41598-023-46899-y -
Journal of the... 2023The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality....
Renin Trajectories and Outcome in Stable Heart Failure with Reduced Ejection Fraction (HFrEF) on Contemporary Therapy: A Monocentric Study from an Austrian Tertiary Hospital Outpatient Clinic.
INTRODUCTION
The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported.
METHODS
A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year.
RESULTS
Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100 iE/ml: 1.01 (95% CI: 0.99-1.02), = 0.414) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), = 0.015). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6 IU/ml, = 0.039, and 122.7 vs. 258.5 IU/ml, = 0.001). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ( = 0.546, = 0.357).
CONCLUSIONS
Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin.
Topics: Humans; Heart Failure; Renin; Stroke Volume; Austria; Disease Progression; Biomarkers; Hospitalization
PubMed: 37941680
DOI: 10.1155/2023/8883145 -
Expert Review of Clinical Pharmacology 2023Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this...
INTRODUCTION
Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA (small interfering ribonucleic acid) therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, and durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach.
AREAS COVERED
This article describes the molecular basis for durability over months and the 24-h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a siRNA targeting hepatic angiotensinogen, which reduces blood pressure (BP) by up to 20 mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran.
EXPERT OPINION
Further studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime BP due to 24-h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran.
Topics: Humans; Angiotensinogen; RNA, Small Interfering; Hypertension; Blood Pressure; Liver
PubMed: 37897397
DOI: 10.1080/17512433.2023.2277330 -
European Heart Journal Dec 2023
Topics: Humans; Angiotensin II; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Hypertension
PubMed: 37889202
DOI: 10.1093/eurheartj/ehad704 -
Combinatorial Chemistry & High... 2024Acute kidney injury (AKI) is one of the most severe complications of sepsis. This study was conducted to analyze the role of urinary neutrophil gelatinase-associated...
Combination of Urinary Neutrophil Gelatinase-associated Lipocalin, Kidney Injury Molecular-1, and Angiotensinogen for the Early Diagnosis and Mortality Prediction of Septic Acute Kidney Injury.
BACKGROUND
Acute kidney injury (AKI) is one of the most severe complications of sepsis. This study was conducted to analyze the role of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary kidney injury molecular-1 (uKIM-1), and urinary angiotensinogen (uAGT) in the early diagnosis and mortality prediction of septic AKI.
METHODS
The prospective study enrolled 80 sepsis patients in the ICU and 100 healthy individuals and divided patients into an AKI group and a non-AKI group. uNGAL, uKIM-1, uAGT, serum creatinine/procalcitonin/C-reaction protein, and other indicators were determined, and clinical prediction scores were recorded. The sensitivity and specificity of uNGAL, uKIM-1, and uAGT in diagnosis and mortality prediction were analyzed by the receiver operator characteristic (ROC) curve and the area under the curve (AUC).
RESULTS
uNGAL, uKIM-1, and uAGT levels were higher in sepsis patients than healthy controls, higher in AKI patients than non-AKI patients, and higher in AKI-2 and AKI-3 patients than AKI-1 patients. At 0 h after admission, the combined efficacy of three indicators in septic AKI diagnosis (ROC-AUC: 0.770; sensitivity: 82.5%; specificity: 70.0%) was better than a single indicator. At 24 h, uNGAL, uKIM-1, and uAGT levels were higher in sepsis non-survivals than survivals and higher in septic AKI non-survivals than septic AKI survivals. The combined efficacy of three indicators in the prediction of sepsis/septic AKI mortality (ROC-AUC: 0.828/0.847; sensitivity: 71.4%/100.0%; specificity: 82.7%/66.7%) was better than a single indicator.
CONCLUSION
uNGAL, uKIM-1, and uAGT levels were increased in septic AKI, and their combination helped the early diagnosis and mortality prediction.
Topics: Humans; Acute Kidney Injury; Sepsis; Angiotensinogen; Male; Female; Middle Aged; Lipocalin-2; Early Diagnosis; Prospective Studies; Hepatitis A Virus Cellular Receptor 1; Aged; Biomarkers; Adult
PubMed: 37855356
DOI: 10.2174/0113862073263073231011060142 -
Arteriosclerosis, Thrombosis, and... Dec 2023Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or... (Review)
Review
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent -acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Topics: Humans; Acetylgalactosamine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering
PubMed: 37855126
DOI: 10.1161/ATVBAHA.123.319897 -
The Canadian Journal of Infectious... 2023SARS-CoV-2 induces apoptosis and amplifies the immune response by continuously stressing the endoplasmic reticulum (ER) after invading cells. This study aimed to...
BACKGROUND
SARS-CoV-2 induces apoptosis and amplifies the immune response by continuously stressing the endoplasmic reticulum (ER) after invading cells. This study aimed to establish a protein-metabolic pathway associated with ER dysfunction based on the invasion mechanism of SARS-CoV-2.
METHODS
This study included 17 healthy people and 46 COVID-19 patients, including 38 mild patients and 8 severe patients. Proteomics and metabolomics were measured in the patient plasma collected at admission and one week after admission. The patients were further divided into the aggravation and remission groups based on disease progression within one week of admission.
RESULTS
Cross-sectional comparison showed that endoplasmic reticulum molecular chaperone-binding immunoglobulin protein (ERC-BiP), angiotensinogen (AGT), ceramide acid (Cer), and C-reactive protein (CRP) levels were significantly increased in COVID-19 patients, while the sphingomyelin (SM) level was significantly decreased ( < 0.05). In addition, longitudinal comparative analysis found that the temporal fold changes of ERC-BiP, AGT, Cer, CRP, and SM were significantly different between the patients in the aggravation and remission groups ( < 0.05). ERC-BiP, AGT, and Cer levels were significantly increased in aggravation patients, while SM was significantly decreased ( < 0.05). Meanwhile, ERC-BiP was significantly correlated with AGT ( = 0.439; < 0.001).
CONCLUSIONS
ERC-BiP can be used as a core index to reflect the degree of ER stress in COVID-19 patients, which is of great value for evaluating the functional state of cells. A functional pathway for AGT/ERC-BiP/glycolysis can directly assess the activation of unfolded protein reactions. The ERC-BiP pathway is closer to the intracellular replication pathway of SARS-CoV-2 and may help in the development of predictive protocols for COVID-19 exacerbation.
PubMed: 37849973
DOI: 10.1155/2023/7253779