SGK, renal function and Hypertension - Europe PMC Article. J Nephrol. Author manuscript; available in PMC 2. May 1. 9. Published in final edited form as: J Nephrol. Nov- Dec; 2. 3(0 1. S1. 24. PMCID: PMC4. NIHMSID: NIHMS5. 76. Department of Physiology, University of Tuebingen, Germany. Department of Pharmacology, University of Tuebingen, Germany. How much fat should you eat on a ketogenic diet? Are you following a ketogenic diet for weight maintenance or weight loss? Depending on the reason, you.Departments of Medicine and Pharmacology, University of California San Diego, VA San Diego Healthcare System, San Diego, USACorresponding author: Florian Lang, Dept. It is activated by insulin and growth factors via phosphatidylinositol- 3- kinase and the 3- phosphoinositide dependent kinase PDK1. SGK1 enhances the activity of a variety of ion channels, such as ENa. C, TRPV5, ROMK, KCNE1/KCNQ1 and Cl. CKb, carriers, such as NHE3, NKCC2, NCC and SGLT1, as well as the Na+/K+- ATPase. SGK1 contributes to Na+ retention and K+ elimination of the kidney as well as mineralocorticoid stimulation of salt appetite. A certain SGK1 gene variant (combined polymorphisms in intron 6 . The SGK1 gene variant has been shown to affect 3–5 % of Caucasians and some 1. Africans. The gene variant sensitizes the carriers to the hypertensive effects of hyperinsulinemia. Moreover, the SGK1 gene variant is associated with increased body mass index, presumably a result of enhanced SGLT1 activity with accelerated intestinal glucose absorption. Obesity predisposes the carriers of the gene variant to development of type II diabetes. Moreover, SGK1 stimulates coagulation. Thus, SGK1 may participate in the pathogenesis of metabolic syndrome or syndrome X, a condition characterized by the coincidence of essential hypertension, procoagulant state, obesity, insulin resistance and hyperinsulinemia. Keywords: blood pressure, obesity, fibrosis, inflammation, coagulation. Introduction. The serum- and glucocorticoid- inducible kinase 1 (SGK1) was originally cloned as an immediate early gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells (1). The human isoform has been discovered as a gene upregulated by cell shrinkage (2). Compelling evidence points to a significant role of SGK1 in the pathophysiology of hypertension. The present brief review thus describes the physiological and pathophysiological impact of SGK1. Due to limited space, the citations had to be restricted and the reader may study a more comprehensive review (3) for more detailed information and earlier publications. Regulation of SGK1 transcription and activity. As reviewed elsewhere (3, 4), SGK1 transcription is stimulated by a wide variety of factors (4) including glucocorticoids, mineralocorticoids. D3 (1,2. 5(OH)2. D3), transforming growth factor . Distinct translational SGK1 isoforms differ in regulation of expression, subcellular localization and function (3, 4). Sgk: an old enzyme revisited. Hyperaldosteronism due to a low-salt diet may induce other forms of Sgk. You have full text access to this OnlineOpen article mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. SGK1 is expressed in a wide variety of organs (3) including the kidney. The subcellular localisation of SGK1 presumably depends on the functional state. Cellular exposure to serum triggers importin- alpha mediated entry of SGK1 into the nucleus (3) whereas activation by hyperosmotic shock or glucocorticoids increases the cytosolic fraction of the kinase (1). SGK1 has further been localized to the mitochondrial membrane (3, 4). Expressed SGK1 is activated by the phosphatidylinositol- 3- kinase (PI3- kinase) pathway involving 3- phosphoinositide (PIP3)- dependent kinase PDK1 and the mammalian target of rapamycin complex 2 TORC2, as well as the serine/threonine kinase WNK1 (with no lysine kinase 1) (3, 4). The PI3- kinase pathway and thus SGK1 is activated by insulin and several growth factors including IGF1 and hepatic growth factor (HGF) (3). Signaling involved in activation of SGK1 further includes bone marrow kinase/extracellular signal- regulated kinase 5 (BK/ERK5) or p. SGK1 is ubiquitinated by the ubiquitin ligase Nedd. Molecular targets of SGK1. SGK1 and related kinases (3) phosphorylate target proteins at the consensus sequence R- X- R- X- X- (S/T)- phi (X = any amino acid, R = arginine, phi = hydrophobic amino acid). The only exclusive targets of SGK1 thus far identified are the N- myc downregulated genes NDRG1 and NDRG2 (3, 4). SGK1 regulates a wide variety of channels, including the renal epithelial Na+ channel ENa. C (Fig. 1), the renal outer medullary K+ channel ROMK1, the Ca. Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A*. Proteinuria in mice expressing PKB/SGK-resistant GSK3. SGK, renal function and. TRPV5,6, the Cl. SGK1 stimulates the Na. Cl cotransporter NCC, the Na+,K+,2. Cl. 1), GLUT1, GLUT4, the amino acid transporters ASCT2, SN1, EAAT1, EAAT2, EAAT3, EAAT4, EAAT5, the peptide transporters Pep. T1/2, the Na+, dicarboxylate cotransporter Na. DC- 1, the creatine transporter Crea. T, the Na+, myoinositol cotransporter SMIT, the phosphate transporter Na. Pi. IIb, and the Na+/K+- ATPase (3, 4, 7–9). Role of SGK1 in the stimulation of renal epithelial Na+ channel ENa. C by aldosterone and intestinal glucose transporter SGLT1 by glucocorticoids. SGK1 regulates channels and carriers in part by direct phosphorylation of the target proteins (3). SGK1 further phosphorylates the ubiquitin ligase Nedd. Phosphorylated Nedd. SGK1 further phosphorylates WNK4, a kinase inhibiting ENa. C activity (3, 4). SGK1 inhibits inducible nitric oxide synthase, thus abrogating the inhibitory effect of NO on ENa. C (3, 4). SGK1 is further effective through activation of the phosphatidylinositol- 3- phosphate- 5- kinase PIKfyve and subsequent formation of PIP2 (3, 4). SGK1 may also influence channel or carrier expression (3, 4). The SGK1 dependent regulation of ENa. C is in part due to impaired SGK1- mediated phosphorylation of Af. ENa. C. SGK1 participates in the regulation of salt intake (1. Accordingly, mineralocorticoids stimulate salt intake in sgk. SGK1 participates in the pathophysiology of metabolic syndrome (see below), allergy, pulmonary hypertension, cardiac hypertrophy, tumor growth and metastasis as well as inflammation and fibrosis (3, 4). SGK1 dependent regulation of renal function. SGK1 contributes to the stimulation of renal Na+ excretion by aldosterone, insulin and IGF1 (3, 4, 1. Part of the effect of aldosterone on ENa. C is independent of SGK1 and effects of aldosterone and SGK1 are in part additive. In contrast, the effects of antidiuretic hormone (ADH) or insulin are fully dependent on SGK1 (1. In SGK1- knockout (sgk. The renal salt loss of sgk. The hyperaldosteronism in sgk. Similarly, despite the lack of SGK1 the colonic ENa. C activity is enhanced in sgk. Inhibition of ENa. C by triamterene leads to eventually lethal salt loss in sgk. The presence of SGK1 is a prerequisite for the antinatriuretic effect of insulin, which is significantly blunted in sgk. The anticalciuria is presumably the result of extracellular volume contraction following renal salt loss due to impaired stimulation of Na. Cl cotransport and ENa. C (3). The volume contraction enhances proximal tubular Na+ and Ca. Ca. 2+ excretion. Pharmacological inhibition of Na. Cl cotransport by thiazide diuretics similarly lead to anticalciuria (2. Ca. 2+ reabsorption (2. Proximal tubular SGK1 expression is low in normal kidneys (3) and SGK1 presumably does not participate in the regulation of proximal tubular transport. Hyperglycemia, however, enhances proximal tubular expression of SGK1, which in turn stimulates renal tubular glucose transport (2. SGK1 expression in glomerular podocytes (2. The proteinuria following DOCA treatment is significantly blunted in SGK1 knockout mice (2. SGK1- dependent renal salt retention contributes to the development of edema during treatment with PPAR. Moreover, enhanced SGK1 expression was found during ascites formation in cirrhotic rats (2. SGK1 sensitive hypertension and metabolic syndrome. Owing to its influence on renal salt excretion and salt intake SGK1 is expected to participate in blood pressure control. Hyperinsulinemia by pretreatment with a high- fructose diet (1. In accordance, the antinatriuretic effect of insulin observed in sgk. Moreover, SGK1 plays a critical role in the hypertensive effects of glucocorticoids (3. In humans a certain variant of the SGK1 gene (the combined presence of distinct polymorphisms in intron 6 . The gene variant affects some 3–5 % of Caucasians (3) and some 1. Africans (3. 1). The gene variant is particularly associated with insulin- sensitivity of blood pressure increase (3. The same SGK1 gene variant is associated with increased body mass index (3). Accordingly, the SGK1 gene variant is more prevalent in patients with type 2 diabetes than in individuals without family history of diabetes (3. The impact of SGK1 on body weight results presumably from the stimulating effect of SGK1 on intestinal glucose absorption, which predisposes to obesity (3). Hypertension, obesity and susceptibility to develop type II diabetes are hallmarks of metabolic syndrome, a condition associated with enhanced morbidity and mortality from cardiovascular disease (3). Metabolic syndrome is associated with enhanced coagulation (3), which is again stimulated by SGK1 (3. Accordingly, SGK1 presumably participates in the pathophysiology of metabolic syndrome. Moreover, maternal SGK1 contributes to fetal programming of hypertension (Fig 2). Protein deficient diet during pregnancy leads to increased blood pressure in offspring only, if the mother expresses SGK1 (3. Role of maternal SGK1 in fetal programming of blood pressure. Conclusions. SGK1 participates in the regulation of renal tubular Na+ reabsorption and intestinal glucose absorption. The kinase thus contributes to blood pressure and body weight control. Accordingly, deranged SGK1 activity could lead to metabolic syndrome. Footnotes. Disclosure: The study in the laboratories of the authors is funded by the Deutsche Forschungsgemeinschaft (DFG to F. L.) and National Institutes of Health (NIH- RO1. HL, Paul, Roland, NIH- R0. DK5. 62. 48 and NIH- P3. DK0. 79. 33. 7 to V. V.). The authors declare that they have no conflict of interest and has been seen and approved by all authors and that it is not under consideration for publication elsewhere. References. 1. Firestone GL, Giampaolo JR, O’Keeffe BA. SGK - Science. Direct Topics. Steroid Hormones such as Aldosterone Bind to Cytoplasmic Receptors and Regulate Nuclear Transcription Events Aldosterone is a steroid hormone that binds to and activates the ineralocorticoid eceptor (MR), which is present in the principal cell, but also in other cell types including intestinal epithelial cells, neuronal cells, and cardiac myocytes. The MR is a member of the steroid/thyroid family of ligand- inducible transcription factors that includes the vitamin D receptor, glucocorticoid receptor, thyroid receptor, and retinoic acid receptor (reviewed in 2. Unlike the transmembrane receptors discussed in the section . The ligand, such as thyroid hormone or aldosterone, can cross the cell membrane, bind the cytosolic receptor, and then translocate as a ligand. In the case of aldosterone, these regulatory sequences are found in the promoter regions of target genes such as SCNN1. A (the ENa. C . In the principal cell, the . The increase in ENa. C . In this manner, aldosterone directly increases the total number of active ENa. C transporters available in the cell, leading to an increase in sodium reabsorptive capacity. A second way in which aldosterone can increase the number of ENa. C channels available to reabsorb sodium is by inhibiting ENa. C degradation. This is mediated by the transcriptional regulation of SGK expression. SGK is a serine- threonine kinase that phosphorylates and inactivates Nedd. At the membrane, the ubiquitin ligase Nedd. ENa. C, targeting it for internalization and proteosomal degradation. Nedd. 4- 2 function is inhibited following phosphorylation by SGK, further increasing ENa. C expression at the cell membrane, and therefore sodium reabsorptive capacity. Vasopressin (AVP), acting through the V2 GPCR, can also increase collecting duct sodium reabsorption. V2 activation leads to c. AMP production and subsequent PKA activation. Like SGK, PKA can phosphorylate and inhibit Nedd. By increasing SGK expression, aldosterone inhibits Nedd. ENa. C degradation, and thereby increases the amount of ENa. C present on the cell surface. Mutations in ENa. C that prevent its association with Nedd. ENa. C expression, resulting in the progressive hypertension seen in Liddle. For membrane channels this typically means a change in the open probability (P) of the channel (the time that the channel spends in the open configuration). ROMK (also known as Kir. TAL, and potassium secretion in the collecting duct (reviewed in 2. One of the major determinants of P for ROMK is the concentration of PIP in the membrane in the vicinity of the channel, an effect that appears to be due to an extensive series of interactions between the basic amino acids in the carboxy terminus of ROMK and the negatively charged head groups of the membrane phospholipids (reviewed in 2. PIP is produced by lipid kinases such as the PI(4)P kinase, and degraded by phospholipases such as PLA and PLC (reviewed in 2. Thus, it is speculated that signals that enhance PIP production or inhibit its degradation will increase ROMK activity at the membrane, whereas pathways that reduce PIP levels, such as activation of PKC, will inhibit its activity. Alterations in the P for ROMK have also been found to be due to direct phosphorylation of the channel by PKA (reviewed in 2. In vitro studies have demonstrated three PKAphosphorylation sites in ROMK, and phosphorylation of two of those sites (serine 2. P for the channel, without changing the number of channels at the membrane. As with other PKA effectors, the presence of the appropriate AKAP is required to target activated PKA to ROMK at the membrane. Although the precise mechanism by which PKA phosphorylation regulates P in ROMK has yet to be determined, it appears that at least part of the effect is due to an increased affinity of ROMK for PIP, thus reducing the concentration of PIP needed to support the channel in the open state. Based on these studies, it is presently believed that the AVP- stimulated increase in thick ascending limb potassium recycling is due to V2- dependent activation of PKA, and subsequent phosphorylation and activation of ROMK. Similar to the regulation of aquaporin- 2 and ENa. C, ROMK can also be regulated by altering channel location or synthesis. Several kinases have been implicated in regulating the trafficking of ROMK, including PKA, SGK, and a recently described kinase WNK (ith o (lysine)). As noted above, there are three PKAphosphorylation sites on ROMK. While two of the sites directly regulate channel open probability, phosphorylation of the third residue (serine 4. In addition to PKA, SGK can phosphorylate ROMK on serine 4. This appears to occur in concert with a scaffolding protein, NHERF2, which increases trafficking of ROMK to the membrane via its interaction with the carboxy terminal PDZ- binding motif. Thus, the increased expression of SGK following aldosterone stimulation can lead to sustained increases in ROMK- dependent potassiumexcretion via increased numbers of channels on the cell membrane. Recently, another family of serine/threonine kinases, the WNKs, have been found to play an important role in regulating the activity of diverse ion channels in the kidney (reviewed in 2. To date there have been four WNK kinases described in humans, all sharing the unusual substitution of a cysteine residue for the more typical lysine in . Mutations of WNK1 and WNK4 have been shown to cause pseudohypoaldosteronism II (PHAII), a syndrome consisting of hypertension with increased sodium reabsorption and hyperkalemia. The mechanisms by which WNKs regulate ROMK and NCC depend on distinct aspects of WNK function. Mutations in WNK1 and WNK4 that cause PHAII result in decreased ROMK at the membrane, and therefore hyperkalemia due to decreased K secretion. It has been shown that ROMK associates with a complex including WNK1, WNK4, and the scaffolding protein intersectin, and that intersectin is required for the endocytosis of ROMK in clathrin- coated vesicles. The formation of this complex is independent of WNK kinase activity, and instead requires the association of proline- rich regions of WNK1 and WNK4 with the SH3 domain of intersectin. Mutations in WNK4 that cause PHAII appear to increase the association of the ROMK. This process is complex and not yet fully elucidated, but appears to involve a balance between WNK4- dependent degradation of NCC and WNK1- dependent activation of NCC that is present on the cell surface (reviewed in 2. In the presence of active WNK4, newly synthesized NCC is targeted via sortilin for lysosomal degradation rather than cell surface expression, thus reducing the pool of NCC available for sodium transport. In contrast, WNK1 and WNK3 activate the sodium transport function of NCC that is on the cell surface by phosphorylating the intracellular kinase SPAK, which then phosphorylates and activates NCC. A second phosphorylation target of WNK3 is WNK4 itself, resulting in inhibition of the WNK4- mediated NCC degradation, and thus increasing NCC surface expression. Mutations in WNK4 that cause PHAII result in increased sodium reabsorption at least in part due to increased NCC on the cell surface.
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