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To address urgent need for strategies to limit mortality from coronavirus disease 2019 (COVID-19), this review describes experimental, clinical and epidemiological evidence that suggests that chronic sub-optimal hydration in the weeks before infection might increase risk of COVID-19 mortality in multiple ways. Sub-optimal hydration is associated with key risk factors for COVID-19 mortality, including older age, male sex, race-ethnicity and chronic disease. Chronic hypertonicity, total body water deficit and/or hypovolemia cause multiple intracellular and/or physiologic adaptations that preferentially retain body water and favor positive total body water balance when challenged by infection. Via effects on serum/glucocorticoid-regulated kinase 1 (SGK1) signaling, aldosterone, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), aquaporin 5 (AQP5) and/or Na+/K+-ATPase, chronic sub-optimal hydration in the weeks before exposure to COVID-19 may conceivably result in: greater abundance of angiotensin converting enzyme 2 (ACE2) receptors in the lung, which increases likelihood of COVID-19 infection, lung epithelial cells which are pre-set for exaggerated immune response, increased capacity for capillary leakage of fluid into the airway space, and/or reduced capacity for both passive and active transport of fluid out of the airways. The hypothesized hydration effects suggest hypotheses regarding strategies for COVID-19 risk reduction, such as public health recommendations to increase intake of drinking water, hydration screening alongside COVID-19 testing, and treatment tailored to the pre-infection hydration condition. Hydration may link risk factors and pathways in a unified mechanism for COVID-19 mortality. Attention to hydration holds potential to reduce COVID-19 mortality and disparities via at least 5 pathways simultaneously.

High prevalence and metastasis rates are characteristics of lung cancer. Glycolysis provides energy for the development and metastasis of cancer cells. The 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3) has been linked to reducing cancer risk and regulates various physiological functions. We hypothesized that 1,25(OH)2D3 could be associated with the expression and activity of Na+/H+ exchanger isoform 1 (NHE1) of Lewis lung cancer cells, thus regulating glycolysis as well as migration by actin reorganization. Followed by online public data analysis, Vitamin D3 receptor, the receptor of 1,25(OH)2D3 has been proved to be abundant in lung cancers. We demonstrated that 1,25(OH)2D3 treatment suppressed transcript levels, protein levels, and activity of NHE1 in LLC cells. Furthermore, 1,25(OH)2D3 treatment resets the metabolic balance between glycolysis and OXPHOS, mainly including reducing glycolytic enzymes expression and lactate production. In vivo experiments showed the inhibition effects on tumor growth as well. Therefore, we concluded that 1,25(OH)2D3 could amend the NHE1 function, which leads to metabolic reprogramming and cytoskeleton reconstruction, finally inhibits the cell migration. [ABSTRACT FROM AUTHOR]

The epithelial Na(+) channel (ENaC) is decisive for sodium reabsorption by the aldosterone-sensitive distal nephron (ASDN) of the kidney. ENaC is regulated by the serum- and glucocorticoid-inducible kinase 1 (SGK1), a kinase genomically upregulated by several hormones including glucocorticoids and mineralocorticoids. SGK1 is activated by the serine/threonine kinase mammalian target of rapamycin (mTOR) isoform mTORC2. SGK1 knockout (sgk1(-/-) mice) impairs renal Na(+) retention during salt depletion. The mTOR catalytic site inhibitor, PP242, but not mTORC1 inhibitor rapamycin, inhibits ENaC, decreases Na(+) flux in isolated perfused tubules and induces natriuresis in wild-type mice. PP242 does not lead to further impairment of Na(+) reabsorption in sgk1(-/-) mice. The mTORC2/SGK1 sensitive renal Na(+) retention leads to extracellular volume expansion with increase of blood pressure. A SGK1 gene variant (prevalence ∼ 3-5% in Caucasians, ∼ 10% in Africans) predisposes to hypertension, stroke, obesity and type 2 diabetes. Future studies will be required to define the role of mTORC2 in the regulation of further SGK1 sensitive transport proteins, such as further ion channels, carriers and the Na(+)/K(+)-ATPase. Moreover, studies are required disclosing the impact of mTORC2 on SGK1 sensitive disorders, such as hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis and tumour growth.

The epithelial Na+ channel (ENaC) is essential for Na+ homeostasis, and dysregulation of this channel underlies many forms of hypertension. Recent studies suggest that mTOR regulates phosphorylation and activation of serum/glucocorticoid regulated kinase 1 (SGK1), which is known to inhibit ENaC internalization and degradation; however, it is not clear whether mTOR contributes to the regulation of renal tubule ion transport. Here, we evaluated the effect of selective mTOR inhibitors on kidney tubule Na+ and K+ transport in WT and Sgk1-/- mice, as well as in isolated collecting tubules. We found that 2 structurally distinct competitive inhibitors (PP242 and AZD8055), both of which prevent all mTOR-dependent phosphorylation, including that of SGK1, caused substantial natriuresis, but not kaliuresis, in WT mice, which indicates that mTOR preferentially influences ENaC function. PP242 also substantially inhibited Na+ currents in isolated perfused cortical collecting tubules. Accordingly, patch clamp studies on cortical tubule apical membranes revealed that mTOR inhibition markedly reduces ENaC activity, but does not alter activity of K+ inwardly rectifying channels (ROMK channels). Together, these results demonstrate that mTOR regulates kidney tubule ion handling and suggest that mTOR regulates Na+ homeostasis through SGK1-dependent modulation of ENaC activity.

USP18 (Ubiquitin-like specific protease 18) is an enzyme cleaving ubiquitin from target proteins. USP18 plays a pivotal role in antiviral and antibacterial immune responses. On the other hand, ubiquitination participates in the regulation of several ion channels and transporters. USP18 sensitivity of transporters has, however, never been reported. The present study thus explored, whether USP18 modifies the activity of the peptide transporters PEPT1 and PEPT2, and whether the peptide transporters are sensitive to the ubiquitin ligase Nedd4-2. To this end, cRNA encoding PEPT1 or PEPT2 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding USP18. Electrogenic peptide (glycine-glycine) transport was determined by dual electrode voltage clamp. As a result, in Xenopus laevis oocytes injected with cRNA encoding PEPT1 or PEPT2, but not in oocytes injected with water or with USP18 alone, application of the dipeptide gly-gly (2 mM) was followed by the appearance of an inward current (Igly-gly). Coexpression of USP18 significantly increased Igly-gly in both PEPT1 and PEPT2 expressing oocytes. Kinetic analysis revealed that coexpression of USP18 increased maximal Igly-gly. Conversely, overexpression of the ubiquitin ligase Nedd4-2 decreased Igly-gly. Coexpression of USP30 similarly increased Igly-gly in PEPT1 expressing oocytes. In conclusion, USP18 sensitive cellular functions include activity of the peptide transporters PEPT1 and PEPT2.