Learning from HBCUs: How to produce Black professionals in STEMM.

Historically Black colleges and universities (HBCUs) offer high-quality education and produce leaders from various backgrounds, mainly being African American. Predominately White institutions can utilize practices that make HBCUs successful to mentor and graduate students of all backgrounds. We also suggest ways to bolster HBCUs so they can train more students.

Chronic use of benzodiazepines: The problem that persists.

Though clinical guidelines and policies discourage the chronic prescribing of benzodiazepines, rates of prescribing have continued to rise in the United States with an estimated 65.9 million office visits per year made for this purpose. Quietly, we have become a nation on benzodiazepines. There are numerous reasons for this discrepancy between official recommendations on the one hand, and actual clinical practice on the other. Drawing from the literature, we argue that while patients and providers both shoulder some of the responsibility, they cannot be solely blamed. Rather, policies and guidelines regarding benzodiazepine prescribing have become out of touch with the clinical reality that benzodiazepines are now deeply entrenched in modern medicine. We propose that guidelines regarding benzodiazepines need to reconsider how to apply concepts such as harm reduction and other lessons learned in the opioid epidemic in order to help physicians manage this increasingly pressing problem affecting millions of Americans.

Podocyte specific deletion of PKM2 ameliorates LPS-induced podocyte injury through beta-catenin.

BACKGROUND: Acute kidney injury (AKI) is associated with a severe decline in kidney function caused by abnormalities within the podocytes' glomerular matrix. Recently, AKI has been linked to alterations in glycolysis and the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2). However, the contribution of this enzyme to AKI remains largely unexplored. METHODS: Cre-loxP technology was used to examine the effects of PKM2 specific deletion in podocytes on the activation status of key signaling pathways involved in the pathophysiology of AKI by lipopolysaccharides (LPS). In addition, we used lentiviral shRNA to generate murine podocytes deficient in PKM2 and investigated the molecular mechanisms mediating PKM2 actions in vitro. RESULTS: Specific PKM2 deletion in podocytes ameliorated LPS-induced protein excretion and alleviated LPS-induced alterations in blood urea nitrogen and serum albumin levels. In addition, PKM2 deletion in podocytes alleviated LPS-induced structural and morphological alterations to the tubules and to the brush borders. At the molecular level, PKM2 deficiency in podocytes suppressed LPS-induced inflammation and apoptosis. In vitro, PKM2 knockdown in murine podocytes diminished LPS-induced apoptosis. These effects were concomitant with a reduction in LPS-induced activation of ß-catenin and the loss of Wilms' Tumor 1 (WT1) and nephrin. Notably, the overexpression of a constitutively active mutant of ß-catenin abolished the protective effect of PKM2 knockdown. Conversely, PKM2 knockdown cells reconstituted with the phosphotyrosine binding-deficient PKM2 mutant (K433E) recapitulated the effect of PKM2 depletion on LPS-induced apoptosis, ß-catenin activation, and reduction in WT1 expression. CONCLUSIONS: Taken together, our data demonstrates that PKM2 plays a key role in podocyte injury and suggests that targetting PKM2 in podocytes could serve as a promising therapeutic strategy for AKI. TRIAL REGISTRATION: Not applicable. Video abstract.

Risk factors for persistent abnormality on chest radiographs at 12-weeks post hospitalisation with PCR confirmed COVID-19.

BACKGROUND: The long-term consequences of COVID-19 remain unclear. There is concern a proportion of patients will progress to develop pulmonary fibrosis. We aimed to assess the temporal change in CXR infiltrates in a cohort of patients following hospitalisation for COVID-19. METHODS: We conducted a single-centre prospective cohort study of patients admitted to University Hospital Southampton with confirmed SARS-CoV2 infection between 20th March and 3rd June 2020. Patients were approached for standard-of-care follow-up 12-weeks after hospitalisation. Inpatient and follow-up CXRs were scored by the assessing clinician for extent of pulmonary infiltrates; 0-4 per lung (Nil = 0, < 25% = 1, 25-50% = 2, 51-75% = 3, > 75% = 4). RESULTS: 101 patients with paired CXRs were included. Demographics: 53% male with a median (IQR) age 53.0 (45-63) years and length of stay 9 (5-17.5) days. The median CXR follow-up interval was 82 (77-86) days with median baseline and follow-up CXR scores of 4.0 (3-5) and 0.0 (0-1) respectively. 32% of patients had persistent CXR abnormality at 12-weeks. In multivariate analysis length of stay (LOS), smoking-status and obesity were identified as independent risk factors for persistent CXR abnormality. Serum LDH was significantly higher at baseline and at follow-up in patients with CXR abnormalities compared to those with resolution. A 5-point composite risk score (1-point each; LOS ≥ 15 days, Level 2/3 admission, LDH > 750 U/L, obesity and smoking-status) strongly predicted risk of persistent radiograph abnormality (0.81). CONCLUSION: Persistent CXR abnormality 12-weeks post COVID-19 was common in this cohort. LOS, obesity, increased serum LDH, and smoking-status were risk factors for radiograph abnormality. These findings require further prospective validation.

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs.

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats.

Women who have bilateral oophorectomies prior to the age of natural menopause are at increased risk of developing mild cognitive decline, dementia, anxiety, and depressive type disorders. Clinical and animal studies indicate angiotensin type 1 receptor (AT1R) blockers (ARBs) have blood pressure (BP)-independent neuroprotective effects. To investigate the potential use of ARBs in normotensive women at increased risk of developing neurocognitive problems, we studied a rat model of bilateral oophorectomy. Long Evans rats were sham-operated (Sham) or ovariectomized (Ovx) at 3 months of age and immediately treated continuously with vehicle (Veh) or the ARB losartan (Los) for the duration of the experiment. In contrast to many hypertensive rat models, ovariectomy did not increase mean arterial pressure (MAP) in these normotensive rats. Ovariectomized rats spent less time in the open arms of the elevated plus maze (EPM) [(% total time): Veh, 34.1 ± 5.1 vs. Ovx, 18.7 ± 4.4; p < 0.05] and in the center of the open field (OF) [(s): Veh, 11.1 ± 1.7 vs. Ovx, 6.64 ± 1.1; p < 0.05]. They also had worse performance in the novel object recognition (NOR) test as evidenced by a reduction in the recognition index [Veh, 0.62 ± 0.04 vs. Ovx, 0.45 ± 0.03; p < 0.05]. These adverse effects of ovariectomy were prevented by Los. Losartan also reduced plasma corticosterone in Ovx rats compared to Veh treatment [(ng/mL): Ovx-Veh, 238 ± 20 vs. Ovx-Los, 119 ± 42; p < 0.05]. Ovariectomy increased AT1R mRNA expression in the CA3 region of the hippocampus (Hc) [(copies x 106/µg RNA): Sham-Veh, 7.15 ± 0.87 vs. Ovx-Veh, 9.86 ± 1.7; p < 0.05]. These findings suggest the neuroprotective effects of this ARB in normotensive Ovx rats involve reduction of plasma corticosterone and blockade of increased AT1R activity in the hippocampus. These data suggest ARBs have therapeutic potential for normotensive women at increased risk of developing cognitive and behavioral dysfunction due to bilateral oophorectomy prior to the natural age of menopause.

Zyflamend induces apoptosis in pancreatic cancer cells via modulation of the JNK pathway.

BACKGROUND: Current pharmacological therapies and treatments targeting pancreatic neuroendocrine tumors (PNETs) have proven ineffective, far too often. Therefore, there is an urgent need for alternative therapeutic approaches. Zyflamend, a combination of anti-inflammatory herbal extracts, that has proven to be effective in various in vitro and in vivo cancer platforms, shows promise. However, its effects on pancreatic cancer, in particular, remain largely unexplored. METHODS: In the current study, we investigated the effects of Zyflamend on the survival of beta-TC-6 pancreatic insulinoma cells (ß-TC6) and conducted a detailed analysis of the underlying molecular mechanisms. RESULTS: Herein, we demonstrate that Zyflamend treatment decreased cell proliferation in a dose-dependent manner, concomitant with increased apoptotic cell death and cell cycle arrest at the G2/M phase. At the molecular level, treatment with Zyflamend led to the induction of ER stress, autophagy, and the activation of c-Jun N-terminal kinase (JNK) pathway. Notably, pharmacological inhibition of JNK abrogated the pro-apoptotic effects of Zyflamend. Furthermore, Zyflamend exacerbated the effects of streptozotocin and adriamycin-induced ER stress, autophagy, and apoptosis. CONCLUSION: The current study identifies Zyflamend as a potential novel adjuvant in the treatment of pancreatic cancer via modulation of the JNK pathway. Video abstract.

Attitudes of primary care physicians toward prescribing buprenorphine: a narrative review.

BACKGROUND: The opioid epidemic is a major public health issue associated with significant overdose deaths. Effective treatments exist, such as the medication buprenorphine, but are not widely available. This narrative review examines the attitudes of primary care providers (PCPs) toward prescribing buprenorphine. METHODS: Narrative review of 20 articles published after the year 2000, using the Consolidated Framework for Implementation Research (CFIR) to organize the findings. RESULTS: Three of the five CFIR domains ("Intervention Characteristics," "Outer Setting," "Inner Setting") were strongly represented in our analysis. Providers were concerned about the clientele associated with buprenorphine, diversion, and their self-efficacy in prescribing the medication. Some believed that buprenorphine does not belong in the discipline of primary care. Other barriers included philosophical objections and stigma toward substance use disorders. Notably, two studies reported a shift in attitudes once physicians prescribed buprenorphine to actual patients. CONCLUSIONS: Negative attitudes toward buprenorphine encompassed multi-layered concerns, ranging from skepticism about the medication itself, the behaviors of patients with opioid use disorders, and beliefs regarding substance use disorders more generally. We speculate, however, that negative attitudes may be improved by tailoring support strategies that address providers' self-efficacy and level of knowledge.

Post-translational modification of the interferon-gamma receptor alters its stability and signaling.

The IFN gamma receptor 1 (IFNGR1) binds IFN-γ and activates gene transcription pathways crucial for controlling bacterial and viral infections. Although decreases in IFNGR1 surface levels have been demonstrated to inhibit IFN-γ signaling, little is known regarding the molecular mechanisms controlling receptor stability. Here, we show in epithelial and monocytic cell lines that IFNGR1 displays K48 polyubiquitination, is proteasomally degraded, and harbors three ubiquitin acceptor sites at K277, K279, and K285. Inhibition of glycogen synthase kinase 3 beta (GSK3ß) destabilized IFNGR1 while overexpression of GSK3ß increased receptor stability. We identified critical serine and threonine residues juxtaposed to ubiquitin acceptor sites that impacted IFNGR1 stability. In CRISPR-Cas9 IFNGR1 generated knockout cell lines, cellular expression of IFNGR1 plasmids encoding ubiquitin acceptor site mutations demonstrated significantly impaired STAT1 phosphorylation and decreased STAT1-dependent gene induction. Thus, IFNGR1 undergoes rapid site-specific polyubiquitination, a process modulated by GSK3ß. Ubiquitination appears to be necessary for efficient IFNGR1-dependent gamma gene induction and represents a relatively uncharacterized regulatory mechanism for this receptor.

Neighborhood Environmental Health and Premature Death From Cardiovascular Disease.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in the United States and disproportionately affects racial/ethnic minority groups. Healthy neighborhood conditions are associated with increased uptake of health behaviors that reduce CVD risk, but minority neighborhoods often have poor food access and poor walkability. This study tested the community-driven hypothesis that poor access to food at the neighborhood level and poor neighborhood walkability are associated with racial disparities in premature deaths from CVD. METHODS: We examined the relationship between neighborhood-level food access and walkability on premature CVD mortality rates at the census tract level for the city of Atlanta using multivariable logistic regression models. We produced maps to illustrate premature CVD mortality, food access, and walkability by census tract for the city. RESULTS: We found significant racial differences in premature CVD mortality rates and geographic disparities in food access and walkability among census tracts in Atlanta. Improved food access and walkability were associated with reduced overall premature CVD mortality in unadjusted models, but this association did not persist in models adjusted for census tract population composition and poverty. Census tracts with high concentrations of minority populations had higher levels of poor food access, poor walkability, and premature CVD mortality. CONCLUSION: This study highlights disparities in premature CVD mortality and neighborhood food access and walkability at the census tract level in the city of Atlanta. Improving food access may have differential effects for subpopulations living in the same area. These results can be used to calibrate neighborhood-level interventions, and they highlight the need to examine race-specific health outcomes.

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung.

Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase.

The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, the NALP3 inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1ß and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1ß in cells. Here we show that LPS increases the NALP3 protein lifespan without significantly altering steady-state mRNA in human cells. LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. A unique small molecule inhibitor of FBXO3 restores FBXL2 levels, resulting in decreased NALP3 protein levels in cells and, thereby, reducing the release of IL-1ß and IL-18 in human inflammatory cells after NALP3 activation. Our findings uncover NALP3 as a molecular target for FBXL2 and suggest that therapeutic targeting of the inflammasome may serve as a platform for preclinical intervention.

Examining the mediating role of cancer-related problems on spirituality and self-rated health among African American cancer survivors: a report from the American Cancer Society's Studies of Cancer Survivors-II.

OBJECTIVE: African American (AA) cancer survivors report poorer self-rated health (SRH) compared to other racial/ethnic groups. Spirituality is often linked to positive health outcomes, with AAs reporting greater levels of spirituality. This study examined the potential mediating role of cancer-related problems in the relationship between spirituality and SRH among AA cancer survivors compared to non-African American (non-AA) survivors. METHODS: We analyzed data on 9006 adult cancer survivors from the American Cancer Society's Study of Cancer Survivors-II. Preliminary analyses compared characteristics of AAs and non-AAs and identified significant covariates of SRH. We tested a path model using multi-group structural equation modeling (SEM), and then examined race as a moderator. RESULTS: Of the three domains of spirituality assessed, AAs had higher levels of peace (p < .001) and faith (p < .001), but not meaning, compared to non-AAs; and of four domains of cancer-related problems assessed, AAs had greater physical distress (p < .001), emotional distress (p < .001), and employment/finance problems (p < .001), but not fear of recurrence. In SEM analyses adjusting for number of comorbidities and income, race moderated the impact of spirituality and cancer-related problems on SRH. Specifically, spirituality had significantly stronger associations with cancer-related problems among AAs than non-AAs. Spirituality was positively associated with all four domains of cancer-related problems, but only physical distress was associated with SRH among AAs. CONCLUSIONS: The negative effects of physical distress may attenuate the positive effects of spirituality on AA's SRH. Future studies should consider racial/ethnic differences in the determinants and conceptualization of SRH, which is a known predictor of survival.

Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells.

Mannan binding lectin (MBL)-associated serine protease type 1 (MASP-1) has a central role in the lectin pathway of complement activation and is required for the formation of C3 convertase. The activity of MASP-1 in the peripheral blood has been identified previously as a highly significant predictor of the severity of liver fibrosis in hepatitis C virus (HCV) infection, but not in liver disease of other aetiologies. In this study we tested the hypotheses that expression of MASP-1 may promote disease progression in HCV disease by direct activation of hepatic stellate cells (HSCs) and may additionally be up-regulated by HCV. In order to do so, we utilized a model for the maintenance of primary human HSC in the quiescent state by culture on basement membrane substrate prior to stimulation. In comparison to controls, recombinant MASP-1 stimulated quiescent human HSCs to differentiate to the activated state as assessed by both morphology and up-regulation of HSC activation markers α-smooth muscle actin and tissue inhibitor of metalloproteinase 1. Further, the expression of MASP-1 was up-regulated significantly by HCV infection in hepatocyte cell lines. These observations suggest a new role for MASP-1 and provide a possible mechanistic link between high levels of MASP-1 and the severity of disease in HCV infection. Taken together with previous clinical observations, our new findings suggest that the balance of MASP-1 activity may be proinflammatory and act to accelerate fibrosis progression in HCV liver disease.

Social support provided by and strain experienced by African-American cancer caregivers.

BACKGROUND: Cancer is the second most common condition among people over 50, behind only dementia, associated with caregiving. As treatments improve, the number of cancer caregivers will increase. However, there is limited research about African-American cancer caregivers (AACCs). PURPOSE: The purpose of this mixed methods study is to describe (1) the types of social support provided by and (2) the levels of strain reported by AACCs. METHODS: Cancer patients from a regional safety net hospital nominated family caregivers who helped them after their cancer diagnosis. Consented caregivers were interviewed in the waiting room while the patient received treatment or later by phone using the Modified Caregiver Strain Index (MCSI), five structured interview questions, and demographic questions-20 min. Responses to the interview questions were processed using Miles and Huberman's content analysis guide. Descriptive statistics for demographics and the MCSI were performed using SPSS. RESULTS: Of the 45 AACCs, 64 % had medical conditions. Caregivers reported patients' pain (31 %), stress (9 %), and nausea (7 %) as the most common symptoms. AACCs most commonly provided instrumental (67 %) or emotional (42 %) support; spiritual (20 %) and informational (20 %) support were less common. CONCLUSION: Emphasis is needed in providing care assistance information to the AACCs to ensure effective support for their loved ones. This study highlights areas of support where assistance can be useful among AACCs.

A Study of Arizona Physician Relocation Patterns by Rurality and Primary Care Status.

BACKGROUND AND OBJECTIVES: Physician location is an important element of health care access. However, physician shortages and disparities in geographic distribution exist. This study examines physician locations, relocation patterns, and factors associated with relocating. METHODS: We used Arizona licensure data and rural-urban commuting area (RUCA) codes to identify Arizona physicians and their office or mailing address locations. Our sample included Arizona physicians estimated to be younger than 70 years of age who had an active license between in 2014 and 2019. We used multivariable logistic regression to assess physicians' adjusted odds of relocating in Arizona by RUCA code, primary care status, age, gender, and medical education location. RESULTS: We identified 11,202 Arizona physicians in our sample, 33% of whom changed practice addresses within Arizona between 2014 and 2019. Primary care physicians (PCPs) in large rural areas had lower odds of relocating in Arizona (0.62, 95% CI 0.43-0.90) than PCPs in urban areas. Compared to 64-69-year-old physicians, those less than 34 and 34-43 years old had statistically higher odds of relocating within Arizona. CONCLUSIONS: Primary care status and rurality are important factors consider to understand physician relocation patterns. We found that a substantial number of Arizona physicians relocated within Arizona between 2014 and 2019, and few of those who relocated (2%) moved to a more rural area.

A Provider-Based Approach to Address Racial Disparities in Lupus Clinical Trial Participation.

OBJECTIVE: Substantial disparities exist in clinical trial participation, which is problematic in diseases such as lupus that disproportionately affect racial/ethnic minority populations. Our objective was to examine the effectiveness of an online educational course aiming to train medical providers to refer Black and Latino patients to lupus clinical trials (LCTs). METHODS: The American College of Rheumatology's Materials to Increase Minority Involvement in Clinical Trials (MIMICT) study used an online, randomized, 2-group, pretest/posttest design with medical and nursing providers of multiple specialties. We exposed intervention group participants to an education course, while the control group participants received no intervention. Controlling for the effects of participant characteristics, including specialty, and professional experience with lupus, we modeled relationships among exposure to the education course and changes in knowledge, attitudes, self-efficacy, and intentions to refer Black and Latino patients to LCTs. We also examined education course satisfaction. RESULTS: Compared to the control group, the intervention group had significantly higher posttest scores for knowledge, self-efficacy, and intentions to refer Black and Latino patients to LCTs. Both medical and nursing trained intervention group participants had significantly higher mean posttest scores for knowledge and intentions to refer compared to the medical and nursing trained control group participants. Attitude was insignificant in analysis. The online education course, which received a favorable summary score, indicated that satisfaction and intentions to refer were strongly and positively correlated. CONCLUSION: The MIMICT education course is an effective method to educate medical providers about LCTs and to improve their intentions to refer Black and Latino patients.

Adenosine A1-receptor knockout mice have a decreased blood pressure response to low-dose ANG II infusion.

Adenosine, acting on A(1)-receptors (A(1)-AR) in the nephron, increases sodium reabsorption, and also increases renal vascular resistance (RVR), via A(1)-ARs in the afferent arteriole. ANG II increases blood pressure and RVR, and it stimulates adenosine release in the kidney. We tested the hypothesis that ANG II-infused hypertension is potentiated by A(1)-ARs' influence on Na(+) reabsorption. Mean arterial pressure (MAP) was measured by radiotelemetry in A(1)-AR knockout mice (KO) and their wild-type (WT) controls, before and during ANG II (400 ng·kg(-1)·min(-1)) infusion. Baseline MAP was not different between groups. ANG II increased MAP in both groups, but on day 12, MAP was lower in A(1)-AR KO mice (KO: 128 ± 3 vs. 139 ± 3 mmHg, P < 0.01). Heart rates were significantly different during days 11-14 of ANG II. Basal sodium excretion was not different (KO: 0.15 ± 0.03 vs. WT: 0.13 ± 0.04 mmol/day, not significant) but was higher in KO mice 12 days after ANG II despite a lower MAP (KO: 0.22 ± 0.03 vs. WT: 0.11 ± 0.02 mmol/day, P < 0.05). Phosphate excretion was also higher in A(1)-AR KO mice on day 12. Renal expression of the sodium-dependent phosphate transporter and the Na(+)/glucose cotransporter were lower in the KO mice during ANG II treatment, but the expression of the sodium hydrogen exchanger isoform 3 was not different. These results indicate that the increase in blood pressure seen in A(1)-AR KO mice is lower than that seen in WT mice but was increased by ANG II nonetheless. The presence of A(1)-ARs during a low dose of ANG II-infusion limits Na(+) and phosphate excretion. This study suggests that A(1)-AR antagonists might be an effective antihypertensive agent during ANG II and volume-dependent hypertension.