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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.

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.

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.