Low Salt Delivery Triggers Autocrine Release of Prostaglandin E2 From the Aldosterone-Sensitive Distal Nephron in Familial Hyperkalemic Hypertension Mice

Aberrant activation of with-no-lysine kinase (WNK)-STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) kinase signaling in the distal convoluted tubule (DCT) causes unbridled activation of the thiazide-sensitive sodium chloride cotransporter (NCC), leading to familial hyperkalemic hypertension (FHHt) in humans. Studies in FHHt mice engineered to constitutively activate SPAK specifically in the DCT (CA-SPAK mice) revealed maladaptive remodeling of the aldosterone sensitive distal nephron (ASDN), characterized by decrease in the potassium excretory channel, renal outer medullary potassium (ROMK), and epithelial sodium channel (ENaC), that contributes to the hyperkalemia. The mechanisms by which NCC activation in DCT promotes remodeling of connecting tubule (CNT) are unknown, but paracrine communication and reduced salt delivery to the ASDN have been suspected. Here, we explore the involvement of prostaglandin E2 (PGE2). We found that PGE2 and the terminal PGE2 synthase, mPGES1, are increased in kidney cortex of CA-SPAK mice, compared to control or SPAK KO mice. Hydrochlorothiazide (HCTZ) reduced PGE2 to control levels, indicating increased PGE2 synthesis is dependent on increased NCC activity. Immunolocalization studies revealed mPGES1 is selectively increased in the CNT of CA-SPAK mice, implicating low salt-delivery to ASDN as the trigger. Salt titration studies in an in vitro ASDN cell model, mouse CCD cell (mCCD-CL1), confirmed PGE2 synthesis is activated by low salt, and revealed that response is paralleled by induction of mPGES1 gene expression. Finally, inhibition of the PGE2 receptor, EP1, in CA-SPAK mice partially restored potassium homeostasis as it partially rescued ROMK protein abundance, but not ENaC. Together, these data indicate low sodium delivery to the ASDN activates PGE2 synthesis and this inhibits ROMK through autocrine activation of the EP1 receptor. These findings provide new insights into the mechanism by which activation of sodium transport in the DCT causes remodeling of the ASDN.

Interventions That Successfully Reduced Adults Salt Intake—A Systematic Review

Background: Adequate sodium intake is important for lowering blood pressure and thus reducing cardiovascular disease risk and other complications. The aim of this review is to identify recent interventions around the world that have been successful in reducing salt intake. Methods: A search in the PubMed, Web of Science and Scopus databases was performed. We include studies published in the last 10 years; randomized trials, pilot intervention without a control arm or experimental study; adult participants; and interventions that successfully reduced salt intake. Study quality was assessed. Results: We included 21 studies, 16 randomized intervention trials and five nonrandomized intervention studies. Eleven interventions described health and nutritional education, seven interventions described nutritional education plus other interventions, and three studies used salt meters to reduce sodium intake. Conclusion: Health and nutritional education, nutritional education plus other interventions and estimates of salt intake showed success in the reduction of salt consumption. There is no evidence that one type of intervention analyzed is more effective than other in reducing salt consumption, so we must analyze each in which individuals or subpopulations will have the intervention performed and use the most suitable approaches to lead to better results.

Review of Reduced Salt, Snow, and Ice Management Practices for Commercial Businesses

Chlorides (frequently sodium chloride) are used to improve safety and access to roads and other surfaces in winter. However, chlorides also pose risks to aquatic life and raises human health concerns as they move to surface waterbodies and infiltrate groundwater. In response, many government bodies have adopted winter maintenance best management practices (BMPs) that reduce the amount of chlorides used while providing service and safety. Commercial businesses maintaining parking lots, driveways, and other surfaces have been shown to contribute as much as 50% of the chloride loads to local waterbodies in some areas, but less is known about the potential benefits of private contractors to implement similar BMPs. In addition, many existing resources on the topic are designed for municipal audiences, creating a knowledge gap about the feasibility of private companies to adopt these practices. The authors identified 14 BMPs common to municipal plans with the potential to be adopted by private contractors through a literature review. These practices aim to increase the efficiency of salt applications, and/or decrease environmental impacts while delivering a similar level of service and cost over time. The authors considered potential barriers and benefits to private contractors adopting and using these BMPs. Benefits included reduced liability (e.g., risk of lawsuits), costs, environmental impacts, and improved service. Barriers included additional staff time and training, increased materials, equipment, and maintenance costs. Additional research is needed to ground-truth these predicted motivations and barriers; a greater understanding of private contractor behaviors can enhance educational efforts that promote reduced salt practices.

Abstract P174: Sex Differences In The Pro-hypertensive Effect Of Carnitine, The Precursor Of Gut-derived Metabolite TMAO

Recent evidence reports sexually divergent mechanisms that differentially drive the severity of hypertension. Our data show that female Dahl Salt-Sensitive (SS) rats are significantly protected from salt-induced hypertension and renal injury and have stark differences in gut microbiota composition compared to males. Gut-derived metabolites are increasingly being recognized as mechanistic links between the gut microbiota and hypertension. One such metabolite is trimethylamine N-oxide (TMAO), which is derived from the bacterial metabolism of carnitine and is gaining notoriety for its role in cardiovascular disease. Metabolomics analysis in high salt-fed SS rats revealed a trend for increased TMAO (1.3-fold, p=0.11) in the serum of males compared to females (n=6). TMAO appears to be specifically derived from gut bacteria since oral antibiotic treatment nearly eliminated circulating TMAO levels in both males and females (99.3% and 88.9% reduction, respectively; p<0.001). Interestingly, antibiotic treatment reduced salt-sensitive hypertension in males but not females. There was also a corresponding increase in the TMAO precursor carnitine (1.9-fold, p<0.01) in the serum of males versus females. Thus, we hypothesized that administration of carnitine (400 mg/kg/day) in the drinking water would exacerbate salt-sensitive hypertension, renal damage, and gut inflammation in male and female SS rats challenged with high salt (4% NaCl). There was a trend for carnitine treatment to exacerbate mean arterial pressure in both males (160±9 vs 146±2 mmHg, n=4-6, p=0.22) and females (155±6 vs 139±2 mmHg, n=2, p=0.14) compared to vehicle. Despite elevated pressure in both sexes, carnitine-treated males exhibited greater increases in albuminuria (340±136 vs 194±29 mg/day, carnitine vs vehicle, p=0.28) than females (55±33 vs 26±5 mg/day). Carnitine treatment also significantly increased the number of CD3+ T cells in the colonic lamina propria (24.3±6.0 vs 2.4±0.5 x 10 6 cells/g tissue, n=5, p<0.05) of male rats compared to vehicle. Together, these data identify gut microbiota-mediated carnitine/TMAO metabolism as a potentially detrimental pathway that promotes greater salt-sensitivity, renal damage, and gut inflammation in males versus females.

A Review Study of a Green Diet and Healthy Ageing

Nowadays people are living longer, and there has been a substantial growth in the global elderly population in the past decades. While life expectancy is increasing, there are growing concerns towards the heavy financial and social burdens related to chronic diseases among the elderly. These have been critical health care issues, and healthy ageing is considered a top priority in public health. Diet and eating habits are crucial factors contributing to healthy ageing. These important aspects have attracted much attention in health research, particularly in consideration of the causes and management of chronic conditions which affect most elder adults in the world. Recently, a growing number of investigations have reported significant findings on the association of reduction in the risks of chronic non-communicable diseases with plant-based diets. Meanwhile, there have been worldwide initiatives and programmes implemented for reduction of salt intake. A green diet, which emphasises the consumption of a diet rich in plant foods with minimal portions of red or processed meat and reduced salt intake, is advocated with due consideration to the importance of sustainable environment and healthy ageing. This paper highlights a brief review of the recent advance of knowledge in diet and health, its effects on the elderly and the significance of a green diet on healthy ageing. Implications for a green diet and recommendations for future research are also discussed.