The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocort...

https://www.physiology.org/doi/pdf/10.1152/physrev.00050.2005

(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms

The serum- and glucocorticoid-regulated kinase (sgk1) is induced by mineralocorticoids and, in turn, upregulates heterologously expressed renal epithelial Na+ channel (ENaC) activity in Xenopus oocytes. Accordingly, Sgk1 is considered to mediate the mineralocorticoid stimulation of renal ENaC activity and antinatriuresis. Here we show that at standard NaCl intake, renal water and electrolyte excretion is indistinguishable in sgk1-knockout (sgk1–/–) mice and wild-type (sgk1+/+) mice. In contrast, dietary NaCl restriction reveals an impaired ability of sgk1–/– mice to adequately decrease Na+ excretion despite increases in plasma aldosterone levels and proximal-tubular Na+ and fluid reabsorption, as well as decreases in blood pressure and glomerular filtration rate.

/pdf/impaired-renal-na-retention-in-the-sgk1-knockout-mouse-2mpfhlsum7.pdf

Impaired renal Na+ retention in the sgk1-knockout mouse

In recent years, it has become evident that the volume of a given cell is an important factor not only in defining its intracellular osmolality and its shape, but also in defining other cellular functions, such as transepithelial transport, cell migration, cell growth, cell death, and the regulation of intracellular metabolism In addition, besides inorganic osmolytes, the existence of organic osmolytes in cells has been discovered Osmolyte transport systems—channels and carriers alike—have been identified and characterized at a molecular level and also, to a certain extent, the intracellular signals regulating osmolyte movements across the plasma membrane The current review reflects these developments and focuses on the contributions of inorganic and organic osmolytes and their transport systems in regulatory volume increase (RVI) and regulatory volume decrease (RVD) in a variety of cells Furthermore, the current knowledge on signal transduction in volume regulation is compiled, revealing an astonishing diversity in transport systems, as well as of regulatory signals The information available indicates the existence of intricate spatial and temporal networks that control cell volume and that we are just beginning to be able to investigate and to understand

/pdf/cell-volume-regulation-osmolytes-osmolyte-transport-and-5c49mpuobo.pdf

Cell volume regulation: osmolytes, osmolyte transport, and signal transduction

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon.

https://link.springer.com/content/pdf/10.1186%2Fs40345-016-0068-y.pdf

Lithium side effects and toxicity: prevalence and management strategies.

We originally discovered the serum and glucocorticoid inducible protein kinase, SGK, as a novel protein kinase that is under acute transcriptional control by serum and glucocorticoids. An expanding set of cell surface receptor, nuclear receptor, and cellular stress pathways has been shown to target SGK, which has implicated this regulated signaling molecule in a variety of biological functions. Compared to most other protein kinases, a distinguishing feature of SGK is the stringent stimulus-dependent regulation of its transcription, subcellular localization and enzymatic activity. In addition, SGK expression is regulated during discrete developmental stages, and during normal and abnormal physiological function. An analysis of the SGK promoter reveals many potential transcription factor sites that potentially account for the stimulus-dependent changes in SGK transcript expression observed in a variety of cell systems, although, the direct stimulus regulation of SGK promoter activity has been established only for glucocorticoids, p53 tumor suppressor protein, hyperosmotic stress and follicle stimulating hormone. In the systems tested to date, hormones, growth factors and environmental cues induce expression of a catalytically active SGK. It is now well established that the enzymatic activity of SGK is controlled by the PI 3-kinase cascade which produces a hyperphosphorylated active SGK. A critical third level of regulation is the stimulus-dependent control of SGK subcellular localization. The nuclear-cytoplasmic shuttling of SGK is regulated by a nuclear localization signal (NLS) that binds to the importin-alpha nuclear import receptor. Modeling of the 3-D structure of the central region of SGK that includes the kinase domain predicts that the NLS is located at an external surface of the molecule. Thus, multiple signal transduction pathways converge on SGK to control its availability, function and access to its substrates and non-substrate targets.

Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity.

Cystic fibrosis (CF) is characterized by impaired Cl(-) secretion and increased Na(+) reabsorption in several tissues including respiratory epithelium. Many CFTR mutations have been identified over the past years. However, only a poor correlation between the genotype and lung phenotype was found suggesting additional factors influencing the phenotype and course of the disease. The serine/threonine kinase SGK1 has recently been shown to stimulate the activity of the epithelial Na(+) channel ENaC. A variety of stimuli such as aldosterone, cell shrinkage, insulin or TGF-beta1 stimulate transcription and activate the SGK1 kinase. Here we further examined the effects of SGK1 on ENaC and CFTR which have mutual interactions and we analyzed sgk1 mRNA abundance in lung tissue from CF patients. Coexpression of CFTR and h-SGK1 in Xenopus oocytes increased ENaC currents as previously described. In addition CFTR mediated currents were also stimulated. h-SGK1 accelerated the expression of the amiloride sensitive Na(+)- current in Xenopus oocytes paralleled by increased ENaC-protein abundance in the oocyte membrane, an effect which was reversed by a h-SGK1(K127R) mutation lacking the ATP-binding site. The cation selectivity or Na(+) affinity were not affected. However, coexpression of h-SGK1 with ENaC altered the sensitivity of the Na(+)-channel to the inhibitors amiloride and triamterene. The inhibitory effect of CFTR expression on ENaC current was not affected by coexpression of h-SGK1 in Xenopus oocytes. Lung tissue from CF patients strongly expressed the serine/threonine kinase h-sgk1 which was not the case for non-CF lung tissue. Loss of CFTR function itself in a CF lung epithelial cell line did not increase SGK1 expression. In summary, enhanced expression of h-SGK1 in epithelial cells of CF-lung tissue may be a novel pathophysiological factor contributing to increased Na(+) channel activity and thus to increased Na(+) transport in CF.

Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis.

When prescribing lithium, the risk of toxicity remains a concern. In this study, we examined a cohort of patients exposed to lithium between 1997 and 2013. The aims of this study were to determine the frequency of lithium intoxication and to evaluate the clinical course and changes in renal function. Of 1340 patients, 96 had experienced at least one episode of lithium levels ⩾1.5 mmol/L, yielding an incidence of 0.01 per patient-year. Seventy-seven patients available for review had experienced 91 episodes, of whom 34% required intensive care and 13% were treated with haemodialysis. There were no fatalities. Acute kidney injury occurred, but renal function at baseline was not different to renal function after the episode. Renal impairment was often associated with co-morbidities and other factors. Both intermittent and continuous-venovenous haemodialysis were used, but the clearance of continuous-venovenous haemodialysis can be too low in cases where large amounts of lithium have been ingested. Saline and forced diuresis have been used and are safe. Lithium intoxication seems rare and can be safely managed in most cases. Physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity.

https://journals.sagepub.com/doi/pdf/10.1177/0269881116652577

Lithium intoxication: Incidence, clinical course and renal function - a population-based retrospective cohort study.

Serotonin syndrome is a toxic state, caused by serotonin (5HT) excess in the central nervous system. Serotonin syndrome’s main feature is neuro-muscular hyperexcitability, which in many cases is mild but in some cases can become life-threatening. The diagnosis of serotonin syndrome remains challenging since it can only be made on clinical grounds. Three diagnostic criteria systems, Sternbach, Radomski and Hunter classifications, are available. Here we test the validity of four assumptions that have become widely accepted: (1) The Hunter classification performs clinically better than the Sternbach and Radomski criteria; (2) in contrast to neuroleptic malignant syndrome, the onset of serotonin syndrome is usually rapid; (3) hyperthermia is a hallmark of severe serotonin syndrome; and (4) serotonin syndrome can readily be distinguished from neuroleptic malignant syndrome on clinical grounds and on the basis of medication history. Systematic review and meta-analysis of all cases of serotonin syndrome and toxicity published between 2004 and 2014, using PubMed and Web of Science. Two of the four assumptions (1 and 2) are based on only one published study each and have not been independently validated. There is little agreement between current criteria systems for the diagnosis of serotonin syndrome. Although frequently thought to be the gold standard for the diagnosis of the serotonin syndrome, the Hunter criteria did not perform better than the Sternbach and Radomski criteria. Not all cases seem to be of rapid onset and only relatively few cases may present with hyperthermia. The 0 differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome is not always clear-cut. Our findings challenge four commonly made assumptions about serotonin syndrome. We propose our meta-analysis of cases (MAC) method as a new way to systematically pool and interpret anecdotal but important clinical information concerning uncommon or emergent phenomena that cannot be captured in any other way but through case reports.

/pdf/conundrums-in-neurology-diagnosing-serotonin-syndrome-a-meta-c8l4tpi503.pdf

Conundrums in neurology : diagnosing serotonin syndrome - a meta-analysis of cases

Background: Lithium remains first choice as maintenance treatment for bipolar affective disorder. Yet, about half of all individuals may stop their treatment at some point, despite lithium’s proven ...

/pdf/reasons-for-lithium-discontinuation-in-men-and-women-with-3u8un51vwm.pdf

Reasons for lithium discontinuation in men and women with bipolar disorder : a retrospective cohort study

Objective: To establish whether lithium or anticonvulsant should be used for maintenance treatment for bipolar affective disorder (BPAD) if the risks of suicide and relapse were traded off against ...

/pdf/a-decision-analysis-of-long-term-lithium-treatment-and-the-3kuuij0q1p.pdf

Michael Ott

Papers

Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis.

Lithium intoxication: Incidence, clinical course and renal function - a population-based retrospective cohort study.

Conundrums in neurology : diagnosing serotonin syndrome - a meta-analysis of cases

Reasons for lithium discontinuation in men and women with bipolar disorder : a retrospective cohort study

A decision analysis of long‐term lithium treatment and the risk of renal failure