Dietary High Salt Intake Exacerbates SGK1-Mediated T Cell Pathogenicity in L-NAME/High Salt-Induced Hypertension.

Sodium chloride (NaCl) activates Th17 and dendritic cells in hypertension by stimulating serum/glucocorticoid kinase 1 (SGK1), a sodium sensor. Memory T cells also play a role in hypertension by infiltrating target organs and releasing proinflammatory cytokines. We tested the hypothesis that the role of T cell SGK1 extends to memory T cells. We employed mice with a T cell deletion of SGK1, SGK1fl/fl × tgCD4cre mice, and used SGK1fl/fl mice as controls. We treated the mice with L-NAME (0.5 mg/mL) for 2 weeks and allowed a 2-week washout interval, followed by a 3-week high-salt (HS) diet (4% NaCl). L-NAME/HS significantly increased blood pressure and memory T cell accumulation in the kidneys and bone marrow of SGK1fl/fl mice compared to knockout mice on L-NAME/HS or groups on a normal diet (ND). SGK1fl/fl mice exhibited increased albuminuria, renal fibrosis, and interferon-γ levels after L-NAME/HS treatment. Myography demonstrated endothelial dysfunction in the mesenteric arterioles of SGK1fl/fl mice. Bone marrow memory T cells were adoptively transferred from either mouse strain after L-NAME/HS administration to recipient CD45.1 mice fed the HS diet for 3 weeks. Only the mice that received cells from SGK1fl/fl donors exhibited increased blood pressure and renal memory T cell infiltration. Our data suggest a new therapeutic target for decreasing hypertension-specific memory T cells and protecting against hypertension.

Pathophysiology and genetics of salt-sensitive hypertension.

Most hypertensive cases are primary and heavily associated with modifiable risk factors like salt intake. Evidence suggests that even small reductions in salt consumption reduce blood pressure in all age groups. In that regard, the ACC/AHA described a distinct set of individuals who exhibit salt-sensitivity, regardless of their hypertensive status. Data has shown that salt-sensitivity is an independent risk factor for cardiovascular events and mortality. However, despite extensive research, the pathogenesis of salt-sensitive hypertension is still unclear and tremendously challenged by its multifactorial etiology, complicated genetic influences, and the unavailability of a diagnostic tool. So far, the important roles of the renin-angiotensin-aldosterone system, sympathetic nervous system, and immune system in the pathogenesis of salt-sensitive hypertension have been studied. In the first part of this review, we focus on how the systems mentioned above are aberrantly regulated in salt-sensitive hypertension. We follow this with an emphasis on genetic variants in those systems that are associated with and/or increase predisposition to salt-sensitivity in humans.

Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges.

We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage.

Corrigendum: The Sweet and Salty Dietary Face of Hypertension and Cardiovascular Disease in Lebanon.

[This corrects the article DOI: 10.3389/fphys.2021.802132.].

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer.

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.

Circulating miRNA as Biomarkers for Colorectal Cancer Diagnosis and Liver Metastasis.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Stage IV CRC patients have poor prognosis with a five-year survival rate of 14%. Liver metastasis is the main cause of mortality in CRC patients. Since current screening tests have several drawbacks, effective stable non-invasive biomarkers such as microRNA (miRNA) are needed. We aim to investigate the expression of miRNA (miR-21, miR-19a, miR-23a, miR-29a, miR-145, miR-203, miR-155, miR-210, miR-31, and miR-345) in the plasma of 62 Lebanese Stage IV CRC patients and 44 healthy subjects using RT-qPCR, as well as to evaluate their potential for diagnosis of advanced CRC and its liver metastasis using the Receiver Operating Characteristics (ROC) curve. miR-21, miR-145, miR-203, miR-155, miR-210, miR-31, and miR-345 were significantly upregulated in the plasma of surgery naïve CRC patients when compared to healthy individuals. We identified two panels of miRNA that could be used for diagnosis of Stage IV CRC (miR-21 and miR-210) with an area under the curve (AUC) of 0.731 and diagnostic accuracy of 69% and liver metastasis (miR-210 and miR-203) with an AUC = 0.833 and diagnostic accuracy of 72%. Panels of specific circulating miRNA, which require further validation, could be potential non-invasive diagnostic biomarkers for CRC and liver metastasis.

The Sweet and Salty Dietary Face of Hypertension and Cardiovascular Disease in Lebanon.

According to the World Health Organization (WHO), an estimated 1.28 billion adults aged 30-79 years worldwide have hypertension; and every year, hypertension takes 7.6 million lives. High intakes of salt and sugar (mainly fructose from added sugars) have been linked to the etiology of hypertension, and this may be particularly true for countries undergoing the nutrition transition, such as Lebanon. Salt-induced hypertension and fructose-induced hypertension are manifested in different mechanisms, including Inflammation, aldosterone-mineralocorticoid receptor pathway, aldosterone independent mineralocorticoid receptor pathway, renin-angiotensin system (RAS), sympathetic nervous system (SNS) activity, and genetic mechanisms. This review describes the evolution of hypertension and cardiovascular diseases (CVDs) in Lebanon and aims to elucidate potential mechanisms where salt and fructose work together to induce hypertension. These mechanisms increase salt absorption, decrease salt excretion, induce endogenous fructose production, activate fructose-insulin-salt interaction, and trigger oxidative stress, thus leading to hypertension. The review also provides an up-to-date appraisal of current intake levels of salt and fructose in Lebanon and their main food contributors. It identifies ongoing salt and sugar intake reduction strategies in Lebanon while acknowledging the country's limited scope of regulation and legislation. Finally, the review concludes with proposed public health strategies and suggestions for future research, which can reduce the intake levels of salt and fructose levels and contribute to curbing the CVD epidemic in the country.