Nanoparticle approaches for the renin-angiotensin system.

The renin-angiotensin system (RAS) is a hormonal cascade that contributes to several disorders: systemic hypertension, heart failure, kidney disease, and neurodegenerative disease. Activation of the RAS can promote inflammation and fibrosis. Drugs that target the RAS can be classified into 3 categories, AT1 angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and renin inhibitors. The therapeutic efficacy of current RAS-inhibiting drugs is limited by poor penetration across the blood-brain barrier, low bioavailability, and to some extent, short half-lives. Nanoparticle-mediated drug delivery systems (DDSs) are possible emerging alternatives to overcome such limitations. Nanoparticles are ideally 1-100 nm in size and are considered efficient DDSs mainly due to their unique characteristics, including water dispersity, prolonged half-life in blood circulation, smaller size, and biocompatibility. Nano-scale DDSs can reduce the drug dosage frequency and acute toxicity of drugs while enhancing therapeutic success. Different types of nanoparticles, such as chitosan, polymeric, and nanofibers, have been examined in RAS-related studies, especially in hypertension, cardiovascular disease, and COVID-19. In this review article, we summarize the physical and chemical characteristics of each nanoparticle to elaborate on their potential use in RAS-related nano-drug delivery research and clinical application.

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer's disease.

Introduction: In a previous retrospective study using postmortem human brain tissues, we demonstrated that loss of Cholinergic Receptor Muscarinic 1 (CHRM1) in the temporal cortex of a subset of Alzheimer's patients was associated with poor survival, whereas similar loss in the hippocampus showed no such association. Mitochondrial dysfunction underlies Alzheimer's pathogenesis. Therefore, to investigate the mechanistic basis of our findings, we evaluated cortical mitochondrial phenotypes in Chrm1 knockout (Chrm1-/-) mice. Cortical Chrm1 loss resulted in reduced respiration, reduced supramolecular assembly of respiratory protein complexes, and caused mitochondrial ultrastructural abnormalities. These mouse-based findings mechanistically linked cortical CHRM1 loss with poor survival of Alzheimer's patients. However, evaluation of the effect of Chrm1 loss on mouse hippocampal mitochondrial characteristics is necessary to fully understand our retrospective human tissue-based observations. This is the objective of this study. Methods: Enriched hippocampal and cortical mitochondrial fractions (EHMFs/ECMFs, respectively) derived from wild-type and Chrm1-/- mice were used to measure respiration by quantifying real-time oxygen consumption, supramolecular assembly of oxidative phosphorylation (OXPHOS)-associated proteins by blue native polyacrylamide gel electrophoresis, post-translational modifications (PTMs) by isoelectric focusing (IEF), and mitochondrial ultrastructure by electron microscopy. Results: In contrast to our previous observations in Chrm1-/- ECMFs, EHMFs of Chrm1-/- mice significantly increased respiration with a concomitant increase in the supramolecular assembly of OXPHOS-associated proteins, specifically Atp5a and Uqcrc2, with no mitochondrial ultrastructural alterations. IEF of ECMFs and EHMFs from Chrm1-/- mice showed a decrease and an increase, respectively in a negatively charged (pH∼3) fraction of Atp5a relative to the wild-type mice, with a corresponding decrease or increase in the supramolecular assembly of Atp5a and respiration indicating a tissue-specific signaling effect. Discussion: Our findings indicate that loss of Chrm1 in the cortex causes structural, and physiological alterations to mitochondria that compromise neuronal function, whereas Chrm1 loss in the hippocampus may benefit neuronal function by enhancing mitochondrial function. This brain region-specific differential effect of Chrm1 deletion on mitochondrial function supports our human brain region-based findings and Chrm1-/- mouse behavioral phenotypes. Furthermore, our study indicates that Chrm1-mediated brain region-specific differential PTMs of Atp5a may alter complex-V supramolecular assembly which in turn regulates mitochondrial structure-function.

Comparative evaluation of biased agonists Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II (SD Ang II) and Sarcosine1 , Isoleucine8 -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors.

Angiotensin II analogue and ß-arrestin biased agonist TRV027 (Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the ß-arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using 125 I-Sarcosine1 , Isoleucine8 -Ang II (125 I-SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT1 receptors. We also compared radioiodinated TRV027 (125 I-SD Ang II) binding affinity for liver AT1 receptors with 125 I-SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and 125 I-SD Ang II had reduced affinity for the AT1 receptor compared with SI Ang II and 125 I-SI Ang II. Additionally, male-female comparisons showed that females have a higher AT1 receptor density, potentially attributed to tissue-dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT1 R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT1 R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism.

CGP42112: the full AT2 receptor agonist and its role in the renin-angiotensin-aldosterone system: no longer misunderstood.

For years, the AT2R-selective ligand CGP42112 has been erroneously characterized as a partial agonist, partly due to its ability to also interact with the AT1R at high concentrations. As late as 2009, it was still being characterized as an antagonist as well. In this perspective/opinion piece, we try to resolve the ambiguity that surrounds the efficacy of this compound by extensively reviewing the literature, tracing its beginnings to 1989, showing that CGP42112 has never been convincingly shown to be a partial agonist or an antagonist at the AT2R. While CGP42112 is now routinely characterized as an AT2R agonist, regrettably, there is a paucity of studies that can validate its efficacy as a full agonist at the AT2R, leaving the door open for continuing speculation regarding the extent of its efficacy. Hopefully, the information presented in this perspective/opinion piece will firmly establish CGP42112 as a full agonist at the AT2R such that it can once again be used as a tool to study the AT2R.

Why Angiotensin II is a Poor Choice for Circulatory Support of Ventilated COVID-19 Patients Compared to Vasopressin.

Early in the COVID-19 pandemic when it was first reported that SARS-CoV-2 used membrane-bound angiotensin-converting enzyme-2 (ACE2) as its receptor for entry into cells, warnings were raised against the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) because of their potential to increase ACE2 expression. These reports ignored the adverse effects that the renin-angiotensin system (RAS) exerts on the cardiovascular system and kidneys via its primary hormone angiotensin (Ang) II acting upon AT1 receptors that could exacerbate the cytokine storm induced by SARS-CoV-2 1. At one point it was even recommended that COVID-19 patients suffering from cardiovascular collapse be administered Ang II to restore blood pressure rather than norepinephrine or vasopressin 2. An alternative strategy for treating COVID-19 was the administration of soluble ACE2 (sACE2) to act as a decoy receptor for the virus, misdirecting it away from vulnerable cells expressing membrane bound ACE2 3-5. However, a paper published in early 2021 6 described a scenario in which sACE2 and vasopressin played essential roles in SARS-CoV-2 infection of cells vulnerable to the virus. This commentary challenges both the 2 and 6 reports based upon their misconceptions and technical errors that pose a threat to the administration of life-saving therapies for severely affected COVID-19 patients.

Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) Protein in the Hippocampus and Temporal Cortex of a Subset of Individuals with Alzheimer's Disease, Parkinson's Disease, or Frontotemporal Dementia: Implications for Patient Survival.

BACKGROUND: Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer's disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. OBJECTIVE: To quantify CHRM1 protein in the postmortem hippocampus and temporal cortex of AD, Parkinson's disease (PD), and frontotemporal dementia (FTD) patients. METHODS: Western blotting was performed on postmortem hippocampus (N = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. RESULTS: Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65-75 years) for both AD and PD patients. CONCLUSION: Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons.

Cholinergic anti-inflammatory pathway and COVID-19.

The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.

Educational initiative in an NCATS TL1 training program to address the impact of systemic racism on human health, biomedical research, and the translational scientist.

Introduction: The goal of clinical and translational science (CTS) is to fill gaps in medical knowledge toward improving human health. However, one of our most pressing challenges does not reside within the biological map we navigate to find sustainable cures but rather the moral compass to recognize and overcome racial and ethnic injustices that continue to influence our society and hinder diverse research rigor. The Georgetown-Howard Universities Center for Clinical and Translational Science includes an inter-institutional TL1-funded training program for predoctoral/postdoctoral trainees in Translational Biomedical Science (TBS). Methods: In the fall of 2020, the TBS program responded to the national social justice crisis by incorporating a curriculum focused on structural racism in biomedical research. Educational platforms, including movie reviews, Journal Clubs, and other workshops, were threaded throughout the curriculum by ensuring safe spaces to discuss racial and ethnic injustices and providing trainees with practical steps to recognize, approach, and respond to these harmful biases in the CTS. Workshops also focused on why individuals underrepresented in science are vital for addressing and closing gaps in CTS. Results: Paring analysis using REDCap software de-identified participants after invitations were sent and collected in the system to maintain anonymity for pre- and post-analysis. The Likert scale evaluated respondents' understanding of diverse scientific circumstances. The pre/Fall and post/Spring surveys suggested this curriculum was successful at raising institutional awareness of racial and ethnic biases. Evaluating the effectiveness of our program with other training Clinical and Translational Science Awards (CTSA) consortiums will strengthen both the academic and professional TBS programs.

Countering the classical renin-angiotensin system.

It is well-established that Ang-(1-7) counteracts the effects of Ang II in the periphery, while stimulating vasopressin release and mimicking the activity of Ang II in the brain, through interactions with various receptors. The rapid metabolic inactivation of Ang-(1-7) has proven to be a limitation to therapeutic administration of the peptide. To circumvent this problem, Alves et al. (Clinical Science (2021) 135(18), https://doi.org/10.1042/CS20210599) developed a new transgenic rat model that overexpresses an Ang-(1-7)-producing fusion protein. In this commentary, we discuss potential concerns with this model while also highlighting advances that can ensue from this significant technical feat.

Alterations in Gene Expression of Renin-Angiotensin System Components and Related Proteins in Colorectal Cancer.

MATERIALS AND METHODS: Quantitative expression of the RNA of these 17 genes in normal and cancerous tissues obtained using chip arrays from the public functional genomics data repository, Gene Expression Omnibus (GEO) application, was compared statistically. RESULTS: Expression of four genes, AGT (angiotensinogen), ENPEP (aminopeptidase A) MME (neprilysin), and PREP (prolyl endopeptidase), was significantly upregulated in CRC specimens. Expression of REN (renin), THOP (thimet oligopeptidase), NLN (neurolysin), PRCP (prolyl carboxypeptidase), ANPEP (aminopeptidase N), and MAS1 (Mas receptor) was downregulated in CRC specimens. CONCLUSIONS: Presuming gene expression parallel protein expression, these results suggest that increased production of the angiotensinogen precursor of angiotensin (ANG) peptides, with the reduction of the enzymes that metabolize it to ANG II, can lead to accumulation of angiotensinogen in CRC tissues. Downregulation of THOP, NLN, PRCP, and MAS1 gene expression, whose proteins contribute to the ACE2/ANG 1-7/Mas axis, suggests that reduced activity of this RAS branch could be permissive for oncogenicity. Components of the RAS may be potential therapeutic targets for treatment of CRC.

Preliminary study of ovariectomy and chronic losartan-induced alterations in brain AT1 receptors.

Women who undergo oophorectomy prior to the age of natural menopause have a higher risk of neurological and psychological impairment. Treatment with the angiotensin receptor blocker (ARB) losartan for 10 weeks following ovariectomy of Long-Evans rats at 3 months of age reduced the ovariectomy-induced cognitive decrements. Following completion of the behavioral experiments, (Campos et al., 2019), the brains were harvested for preliminary receptor autoradiographic studies of AT1 receptor (AT1R) binding in selected brain regions using quantitative densitometric analysis of autoradiograms of 125I-sarcosine1, isoleucine8 angiotensin II binding. Four of the brain regions (amygdala, ventral subiculum, piriform cortex, and cingulate cortex) are associated with cognitive and emotional behavior while one (lateral hypothalamus) is associated with homeostasis. The density of AT1R varied by region: ventral subiculum > amygdala and cingulate cortex, and piriform cortex > cingulate cortex. Losartan treatment decreased AT1R binding in the ventral subiculum of sham and ovariectomized rats by 41.6%, and 46% in the piriform cortex of the sham rats, but tended to increase AT1R binding in the piriform cortex and cingulate cortex 77% and 107%, respectively, in the ovariectomized rats. AT1R binding did not differ significantly between intact male and sham-vehicle female rats among surveyed brain regions. These results suggest that losartan-induced changes in brain AT1R expression may contribute to the reduced anxiety-like behavior and memory impairments seen in ovariectomized rats, but replication of these observations will be needed to determine the extent to which brain AT1R changes mediate the adverse behavioral effects of ovariectomy.

Chronic administration of pharmacological doses of angiotensin 1-7 and iodoangiotensin 1-7 has minimal effects on blood pressure, heart rate, and cognitive function of spontaneously hypertensive rats.

Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1-7 (Ang 1-7), a product of the renin-angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. Recent data from our lab reveals that the addition of a non-radioactive iodine molecule to the tyrosine in position 4 of Ang 1-7 (iodoAng 1-7) makes it ~1000-fold more potent than Ang 1-7 in competing for the 125 I-Ang 1-7 binding site (Stoyell-Conti et al., 2020). Moreover, the addition of the non-radioactive iodine molecule increases (~4-fold) iodoAng 1-7's ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1-7 can also compete for the 125 I-Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1-7 (non-radioactive iodine isotope) and Ang 1-7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1-7, or iodoAng 1-7 administrated subcutaneously using a 28-day osmotic mini pump. Systolic BP was measured non-invasively by the tail-cuff technique. Cognitive function was assessed by Y-Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1-7 prevented the increase in heart rate with age, while Ang 1-7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1-7 nor iodoAng 1-7 administered subcutaneously affected BP nor cognitive function.

Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19.

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in Ace2 knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.

Modulation of the rat angiotensin type 1a receptor by an upstream short open reading frame.

The rat angiotensin type 1a receptor (AT1aR) is a peptide hormone G protein-coupled receptor (GPCR) that plays a key role in electrolyte homeostasis and blood pressure control. There is a highly conserved short open reading frame (sORF) in exon 2 (E2) that is downstream from exon 1 (E1) and upstream of the AT1aR coding region located in exon 3 (E3). To determine the role of this E2 sORF in AT1aR signaling, human embryonic kidney-293 (HEK293) cells were transfected with plasmids containing AT1aR cDNA with either an intact or disrupted E2 sORF. The intact sORF attenuated the efficacy of angiotensin (Ang) II (p < 0.001) and sarcosine1,Ile4,Ile8-Ang II (SII), (p < 0.01) to activate AT1aR signaling through extracellular signal-related kinases 1/2 (ERK1/2). A time-course showed agonist-induced AT1aR-mediated ERK1/2 activation was slower in the presence of the intact compared to the disrupted sORF [Ang II: p < 0.01 and SII: p < 0.05]. Ang II-induced ERK1/2 activation was completely inhibited by the protein kinase C (PKC) inhibitor Ro 31-8220 regardless of whether the sORF was intact or disrupted. Flow cytometric analyses suggested the intact sORF improved cell survival; the percentage of live cells increased (p < 0.05) while the percentage of early apoptotic cells decreased (p < 0.01) in cells transfected with the AT1aR plasmid containing the intact sORF. These findings have implications for the regulation of AT1Rs in physiological and pathological conditions and warrant investigation of sORFs in the 5' leader sequence (5'LS) of other GPCRs.

125I-Angiotensin 1-7 binds to a different site than angiotensin 1-7 in tissue membrane preparations.

PURPOSE: To study the receptor for Angiotensin (Ang) 1-7 using a radioligand (125I-Ang 1-7)-binding assay. For more than a decade, Mas has been viewed as the receptor for Ang 1-7; however, Ang 1-7 binding has not been pharmacologically characterized in tissue membrane preparations. METHODS: Radioligand-binding assays were carried out using tissue membrane preparations using radioiodinated Angiotensin 1-7 (125I-Ang 1-7) to characterize its binding site. Non-radioactive 127I-Ang 1-7 was used to test if the addition of an iodine to the tyrosine4 moiety of Ang 1-7 changes the ability of Ang 1-7 to competitively inhibit 125I-Ang 1-7 binding. RESULTS: 125I-Ang 1-7 binds saturably, with moderately high affinity (10-20 nM) to a binding site in rat liver membranes that is displaceable by 127I-Ang 1-7 at nanomolar concentrations (IC50 = 62 nM) while Ang 1-7 displaces at micromolar concentrations (IC50 = 80 µM) at ~22 °C. This binding was also displaceable by inhibitors of metalloproteases at room temperature. This suggests that 125I-Ang 1-7 binds to MMPs and/or ADAMs as well as other liver membrane elements at ~ 22 °C. However, when 125I-Ang 1-7-binding assays were run at 0-4 °C, the same MMP inhibitors did not effectively compete for 125I-Ang 1-7. CONCLUSIONS: The addition of an iodine molecule to the tyrosine in position 4 of Ang 1-7 drastically changes the binding characteristics of this peptide making it unsuitable for characterization of Ang 1-7 receptors.

Metabolism of angiotensin peptides by angiotensin converting enzyme 2 (ACE2) and analysis of the effect of excess zinc on ACE2 enzymatic activity.

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT1 Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp1Ang II, 2-8 heptapeptide) and Ang IV (des-Asp1des-Arg2Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest Km) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 µM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.

The role of the brain renin-angiotensin system (RAS) in mild traumatic brain injury (TBI).

There is considerable interest in traumatic brain injury (TBI) induced by repeated concussions suffered by athletes in sports, military personnel from combat-and non-combat related activities, and civilian populations who suffer head injuries from accidents and domestic violence. Although the renin-angiotensin system (RAS) is primarily a systemic cardiovascular regulatory system that, when dysregulated, causes hypertension and cardiovascular pathology, the brain contains a local RAS that plays a critical role in the pathophysiology of several neurodegenerative diseases. This local RAS includes receptors for angiotensin (Ang) II within the brain parenchyma, as well as on circumventricular organs outside the blood-brain-barrier. The brain RAS acts primarily via the type 1 Ang II receptor (AT1R), exacerbating insults and pathology. With TBI, the brain RAS may contribute to permanent brain damage, especially when a second TBI occurs before the brain recovers from an initial injury. Agents are needed that minimize the extent of injury from an acute TBI, reducing TBI-mediated permanent brain damage. This review discusses how activation of the brain RAS following TBI contributes to this damage, and how drugs that counteract activation of the AT1R including AT1R blockers (ARBs), renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and agonists at type 2 Ang II receptors (AT2) and at Ang (1-7) receptors (Mas) can potentially ameliorate TBI-induced brain damage.