Alejandro M Bertorello

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (105)586.4 Total impact

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    ABSTRACT: Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1(+/+) mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-β1-signaling inhibition.
    Circulation Research 01/2015; 116(4). DOI:10.1161/CIRCRESAHA.116.304529 · 11.02 Impact Factor
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    ABSTRACT: Cardiac left ventricle hypertrophy (LVH) constitutes a major risk factor for heart failure. Although LVH is most commonly caused by chronic elevation in arterial blood pressure, reduction of blood pressure to normal levels does not always result in regression of LVH, suggesting that additional factors contribute to the development of this pathology. We tested whether genetic preconditions associated with the imbalance in sodium homeostasis could trigger the development of LVH without concomitant increases in blood pressure. The results showed that the presence of a hypertensive variant of α-adducin gene in Milan rats (before they become hypertensive) resulted in elevated expression of genes associated with LVH, and of salt-inducible kinase 2 (SIK2) in the left ventricle (LV). Moreover, the mRNA expression levels of SIK2, α-adducin, and several markers of cardiac hypertrophy were positively correlated in tissue biopsies obtained from human hearts. In addition, we found in cardiac myocytes that α-adducin regulates the expression of SIK2, which in turn mediates the effects of adducin on hypertrophy markers gene activation. Furthermore, evidence that SIK2 is critical for the development of LVH in response to chronic high salt diet (HS) was obtained in mice with ablation of the sik2 gene. Increases in the expression of genes associated with LVH, as well as increases in LV wall thickness upon HS, occurred only in sik2+/+ but not in sik2-/- mice. Thus LVH triggered by HS or the presence of a genetic variant of α-adducin requires SIK2 and is independent of elevated blood pressure. Inhibitors of SIK2 may constitute part of a novel therapeutic regimen aimed at prevention/regression of LVH.
    PLoS ONE 04/2014; 9(4):e95771. DOI:10.1371/journal.pone.0095771 · 3.23 Impact Factor
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    ABSTRACT: To uncover the potential cardiovascular effects of human polymorphisms influencing transforming growth factor β1 (TGFβ1) expression, we generated mice with Tgfb1 mRNA expression graded in five steps from 10% to 300% normal. Adrenal expression of the genes for mineralocorticoid-producing enzymes ranged from 50% normal in the hypermorphs at age 12 wk to 400% normal in the hypomorphs accompanied with proportionate changes in plasma aldosterone levels, whereas plasma volumes ranged from 50% to 150% normal accompanied by marked compensatory changes in plasma angiotensin II and renin levels. The aldosterone/renin ratio ranged from 0.3 times normal in the 300% hypermorphs to six times in the 10% hypomorphs, which have elevated blood pressure. Urinary output of water and electrolytes are markedly decreased in the 10% hypomorphs without significant change in the glomerular filtration rate. Renal activities for the Na(+), K(+)-ATPase, and epithelial sodium channel are markedly increased in the 10% hypomorphs. The hypertension in the 10% hypomorphs is corrected by spironolactone or amiloride at doses that do not change blood pressure in wild-type mice. Thus, changes in Tgfb1 expression cause marked progressive changes in multiple systems that regulate blood pressure and fluid homeostasis, with the major effects being mediated by changes in adrenocortical function.
    Proceedings of the National Academy of Sciences 03/2013; 110(14). DOI:10.1073/pnas.1302641110 · 9.67 Impact Factor
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    ABSTRACT: The salt-inducible kinase 1 (SIK1) network constitutes an alternative target by which agents can modulate active sodium transport in renal epithelia and avoid the increases in systemic blood pressure. SIK1 associates with the plasma membrane Na+,K+-ATPase regulatory network and controls its catalytic activity upon increases in intracellular sodium. The aim of this study was to evaluate the role of SIK1 upon Na+ transporters and transepithelial electrical resistance using an epithelial cell line derived from mouse lung, MLE-12, stably transfected with SIK1-shRNA or with a scrambled shRNA. Normal MLE-12 cells formed tight monolayers; however, MLE-12 cells lacking SIK1 have a significantly lower transepithelial resistant than cells expressing normal levels of SIK1 protein. MLE-12 expressing SIK-shRNA had a significant reduction in Na+,K+-ATPase catalytic activity and it was paralleled by a reduction in the Na+/H+-exchanger activity. Cl-/HCO3- exchanger activity remained unchanged. Similarly, the plasma membrane potential was lower in cells lacking SIK1, and these cells did not exhibit depolarization in response to ouabain, and a change of less magnitude in response to KCL. The levels of intracellular ATP were higher in MLE-12 cells lacking SIK1, most likely due to a reduced consumption (lower Na+,K+-ATPase activity). These results highlight the potential role of SIK1 in controlling the integrity and function of polarized epithelia. Moreover, further insight into the regulation of SIK1 may enable the development of novel drugs to prevent or treat cardiovascular disorders and edema formation states.
    Journal of Hypertension 09/2012; 30:e87. DOI:10.1097/01.hjh.0000420181.90311.e8 · 4.72 Impact Factor
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    ABSTRACT: Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3(-/-) mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3(-/-) mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3(-/-) mice. Lipid metabolism disorders in Sik3(-/-) mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice.
    PLoS ONE 05/2012; 7(5):e37803. DOI:10.1371/journal.pone.0037803 · 3.23 Impact Factor
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    ABSTRACT: The protein kinase liver kinase B1 (LKB1) regulates cell polarity and intercellular junction stability. Also, LKB1 controls the activity of salt-inducible kinase 1 (SIK1). The role and relevance of SIK1 and its downstream effectors in linking the LKB1 signals within these processes are partially understood. We hypothesize that SIK1 may link LKB1 signals to the maintenance of epithelial junction stability by regulating E-cadherin expression. Results from our studies using a mouse lung alveolar epithelial (MLE-12) cell line or human renal proximal tubule (HK2) cell line transiently or stably lacking the expression of SIK1 (using SIK1 siRNAs or shRNAs), or with its expression abrogated (sik1(+/+) vs. sik1(-/-) mice), indicate that suppression of SIK1 (∼40%) increases the expression of the transcriptional repressors Snail2 (∼12-fold), Zeb1 (∼100%), Zeb2 (∼50%), and TWIST (∼20-fold) by activating cAMP-response element binding protein. The lack of SIK1 and activation of transcriptional repressors decreases the availability of E-cadherin (mRNA and protein expression by ∼100 and 80%, respectively) and the stability of intercellular junctions in epithelia (decreases in transepithelial resistance). Furthermore, LKB1-mediated increases in E-cadherin expression are impaired in cells where SIK1 has been disabled. We conclude that SIK1 is a key regulator of E-cadherin expression, and thereby contributes to the stability of intercellular junctions.
    The FASEB Journal 04/2012; 26(8):3230-9. DOI:10.1096/fj.12-205609 · 5.04 Impact Factor
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    ABSTRACT: Cardiac hypertrophy (CH) generally occurs as the result of the sustained mechanical stress caused by elevated systemic arterial blood pressure (BP). However, in animal models, elevated salt intake is associated with CH even in the absence of significant increases in BP. We hypothesize that CH is not exclusively the consequence of mechanical stress but also of other factors associated with elevated BP such as abnormal cell sodium homeostasis. We examined the effect of small increases in intracellular sodium concentration ([Na(+)](i)) on transcription factors and genes associated with CH in a cardiac cell line. Increases in [Na(+)](i) led to a time-dependent increase in the expression levels of mRNA for natriuretic peptide and myosin heavy chain genes and also increased myocyte enhancer factor (MEF)2/nuclear factor of activated T cell (NFAT) transcriptional activity. Increases in [Na(+)](i) are associated with activation of salt-inducible kinase 1 (snflk-1, SIK1), a kinase known to be critical for cardiac development. Moreover, increases in [Na(+)](i) resulted in increased SIK1 expression. Sodium did not increase MEF2/NFAT activity or gene expression in cells expressing a SIK1 that lacked kinase activity. The mechanism by which SIK1 activated MEF2 involved phosphorylation of HDAC5. Increases in [Na(+)](i) activate SIK1 and MEF2 via a parallel increase in intracellular calcium through the reverse mode of Na(+)/Ca(2+)-exchanger and activation of CaMK1. These data obtained in a cardiac cell line suggest that increases in intracellular sodium could influence myocardial growth by controlling transcriptional activation and gene expression throughout the activation of the SIK1 network.
    AJP Heart and Circulatory Physiology 03/2012; 303(1):H57-65. DOI:10.1152/ajpheart.00512.2011 · 3.84 Impact Factor

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    ABSTRACT: Distinct forms of MEF2 transcription factor act as positive or negative regulators of dendritic spine formation, with MEF2C playing a key regulator role in synapse plasticity. We report here that acute cocaine treatment of rats induced the expression of MEF2C in the striatum through a recently discovered transduction pathway. Repeated injections were found to induce MEF2C to a lesser extent. The mechanism by which MEF2C was induced involves the subsequent activation of the salt-inducible kinase SIK1 and the phosphorylation of HDAC5, a member of the class IIa of HDACs. Cocaine activated SIK1 by phosphorylation on Thr-182 residue, which was accompanied by the nuclear import of the kinase. In the nuclear compartment, SIK1 then phosphorylated HDAC5 causing the shuttling of its phospho-form from the nucleus to the cytoplasm of striatal cells. Activation of SIK1 by cocaine was further validated by the phosphorylation of TORC1/3, which was followed by the shuttling of TORC proteins from the nucleus to the cytoplasm. Activation of MEF2C was assessed by measuring the expression of the MEF2C gene itself, since the gene is known to be under the control of its own product. Since MEF2C plays a key role in memory/learning processes, activation of this pathway by cocaine is probably involved in plasticity mechanisms whereby the drug establishes its long-term effects such as drug dependence.
    Synapse 01/2012; 66(1):61-70. DOI:10.1002/syn.20988 · 2.13 Impact Factor
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    ABSTRACT: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.
    PLoS ONE 12/2011; 6(12):e29523. DOI:10.1371/journal.pone.0029523 · 3.23 Impact Factor
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    ABSTRACT: Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5' adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na(+),K(+)-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na(+),K(+)-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation. Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na(+),K(+)-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype-phenotype association studies were performed in three Swedish and one Japanese population-based cohorts. SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change (15)Gly→Ser in the SIK1 protein. SIK1-(15)Ser was found to increase plasma membrane Na(+),K(+)-ATPase activity in cultured VSMC line from rat aorta. Genotype-phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for (15)Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048). The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.
    Journal of Hypertension 10/2011; 29(12):2395-403. DOI:10.1097/HJH.0b013e32834d3d55 · 4.72 Impact Factor
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    ABSTRACT: The Na+,K+-ATPase (Na:Kpump) is an integral membrane protein responsible for maintaining the gradients of sodium and potassium across the plasma membrane1. These gradients constitute the basis for resting membrane potential permitting membrane excitability in neurons2, and control indirectly diverse secretory processes, such as that of insulin from pancreatic β-cells3.
    Acute Respiratory Distress Syndrome, 07/2011: pages 45-52;
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    ABSTRACT: Salt-inducible kinase 1 (SIK1) in epithelial cells mediates the increases in active sodium transport (Na(+), K(+)-ATPase-mediated) in response to elevations in the intracellular concentration of sodium. In lung alveolar epithelial cells increases in active sodium transport in response to β-adrenergic stimulation increases pulmonary edema clearance. Therefore, we sought to determine whether SIK1 is present in lung epithelial cells and to examine whether isoproterenol-dependent stimulation of Na(+), K(+)-ATPase is mediated via SIK1 activity. All three SIK isoforms were present in airway epithelial cells, and in alveolar epithelial cells type 1 and type 2 from rat and mouse lungs, as well as from human and mouse cell lines representative of lung alveolar epithelium. In mouse lung epithelial cells, SIK1 associated with the Na(+), K(+)-ATPase α-subunit, and isoproterenol increased SIK1 activity. Isoproterenol increased Na(+), K(+)-ATPase activity and the incorporation of Na(+), K(+)-ATPase molecules at the plasma membrane. Furthermore, those effects were abolished in cells depleted of SIK1 using shRNA, or in cells overexpressing a SIK1 kinase-deficient mutant. These results provide evidence that SIK1 is present in lung epithelial cells and that its function is relevant for the action of isoproterenol during regulation of active sodium transport. As such, SIK1 may constitute an important target for drug discovery aimed at improving the clearance of pulmonary edema.
    Biochemical and Biophysical Research Communications 05/2011; 409(1):28-33. DOI:10.1016/j.bbrc.2011.04.100 · 2.30 Impact Factor
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    Ariel Jaitovich · Alejandro M Bertorello ·
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    ABSTRACT: Sodium is the main determinant of body fluid distribution. Sodium accumulation causes water retention and, often, high blood pressure. At the cellular level, the concentration and active transport of sodium is handled by the enzyme Na(+),K(+)-ATPase, whose appearance enabled evolving primitive cells to cope with osmotic stress and contributed to the complexity of mammalian organisms. Na(+),K(+)-ATPase is a platform at the hub of many cellular signaling pathways related to sensing intracellular sodium and dealing with its detrimental excess. One of these pathways relies on an intracellular sodium-sensor network with the salt-inducible kinase 1 (SIK1) at its core. When intracellular sodium levels rise, and after the activation of calcium-related signals, this network activates the Na(+),K(+)-ATPase and expel the excess of sodium from the cytosol. The SIK1 network also mediates sodium-independent signals that modulate the activity of the Na(+),K(+)-ATPase, like dopamine and angiotensin, which are relevant per se in the development of high blood pressure. Animal models of high blood pressure, with identified mutations in components of multiple pathways, also have alterations in the SIK1 network. The introduction of some of these mutants into normal cells causes changes in SIK1 activity as well. Some cellular processes related to the metabolic syndrome, such as insulin effects on the kidney and other tissues, also appear to involve the SIK1. Therefore, it is likely that this protein, by modulating active sodium transport and numerous hormonal responses, represents a "crossroad" in the development and adaptation to high blood pressure and associated diseases.
    Biochimica et Biophysica Acta 03/2010; 1802(12):1140-9. DOI:10.1016/j.bbadis.2010.03.009 · 4.66 Impact Factor
  • Ariel Jaitovich · Alejandro M Bertorello ·
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    ABSTRACT: Chronic hypertension is characterized by a persistent increase in vascular tone. Sodium-rich diets promote hypertension; however, the underlying molecular mechanisms are not fully understood. Variations in the sodium content of the diet, through hormonal mediators such as dopamine and angiotensin II, modulate renal tubule Na(+),K(+)-ATPase activity. Stimulation of Na(+),K(+)-ATPase activity increases sodium transport across the renal proximal tubule epithelia, promoting Na(+) retention, whereas inhibited Na(+),K(+)-ATPase activity decreases sodium transport, and thereby natriuresis. Diets rich in sodium also enhance the release of adrenal endogenous ouabain-like compounds (OLC), which inhibit Na(+),K(+)-ATPase activity, resulting in increased intracellular Na(+) and Ca(2+) concentrations in vascular smooth muscle cells, thus increasing the vascular tone, with a corresponding increase in blood pressure. The mechanisms by which these homeostatic processes are integrated in response to salt intake are complex and not completely elucidated. However, recent scientific findings provide new insights that may offer additional avenues to further explore molecular mechanisms related to normal physiology and pathophysiology of various forms of hypertension (i.e. salt-induced). Consequently, new strategies for the development of improved therapeutics and medical management of hypertension are anticipated.
    Life sciences 11/2009; 86(3-4):73-8. DOI:10.1016/j.lfs.2009.10.019 · 2.70 Impact Factor
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    Karin Stenström · Hiroshi Takemori · Giuseppe Bianchi · Adrian I Katz · Alejandro M Bertorello ·
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    ABSTRACT: Because a newly described salt-inducible kinase 1 (SIK1) network is responsible for increases in active cell sodium transport in response to elevated intracellular sodium, we hypothesized that this network could mediate the effects of the mutant (hypertensive) form of alpha-adducin on Na,K-ATPase activity. Studies were performed in normotensive and hypertensive Milan rats and in a cell line of proximal tubule origin expressing transiently variants of alpha-adducin (human G460W/S586C; rat F316Y) that are associated with elevated blood pressure and result in increased Na,K-ATPase activity. Na,K-ATPase activity was determined as ouabain-sensitive rubidium transport. SIK1 activity (T182 phosphorylation) was significantly elevated in renal proximal tubule cells from Milan hypertensive rats (carrying a alpha-adducin mutation) when compared with normotensive controls. Similarly, SIK1 activity (T182 phosphorylation) was elevated in a normal renal proximal tubule cell line when transfected with the alpha-adducin variant carrying the human hypertensive mutation. Blocking the SIK1 network using negative mutants as well as different stages of its activation pathway prevented the effects induced by the hypertensive alpha-adducin. The SIK1 network may constitute an alternative target by which agents can modulate active sodium transport in renal epithelia and avoid the increases in systemic blood pressure that are associated with genetic mutations in the human alpha-adducin molecule.
    Journal of Hypertension 09/2009; 27(12):2452-7. DOI:10.1097/HJH.0b013e328330cf15 · 4.72 Impact Factor
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    Z Chen · I Leibiger · AI Katz · A M Bertorello ·
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    ABSTRACT: Dopamine inhibits renal cell Na(+),K(+)-ATPase activity and cell sodium transport by promoting the internalization of active molecules from the plasma membrane, whereas angiotensin II (ATII) stimulates its activity by recruiting new molecules to the plasma membrane. They achieve such effects by activating multiple and distinct signalling molecules in a hierarchical manner. The purpose of this study was to investigate whether dopamine and ATII utilize scaffold organizer proteins as components of their signalling networks, in order to avoid deleterious cross talk. Attention was focused on a multiple PDZ domain protein, Pals-associated tight junction protein (PATJ). Ectopic expression of PATJ in renal epithelial cells in culture was used to study its interaction with components of the dopamine signalling cascade. Similarly, expression of PATJ deletion mutants was employed to analyse its functional relevance during dopamine-, ATII- and insulin-dependent regulation of Na(+),K(+)-ATPase. Dopamine receptors and components of its signalling cascade mediating inhibition of Na(+),K(+)-ATPase interact with PATJ. Inhibition of Na(+),K(+)-ATPase by dopamine was prevented by expression of mutants of PATJ lacking PDZ domains 2, 4 or 5; whereas the stimulatory effect of ATII and insulin on Na(+),K(+)-ATPase was blocked by expression of PATJ lacking PDZ domains 1, 4 or 5. A multiple PDZ domain protein may add functionality to G protein-coupled and tyrosine kinase receptors signalling during regulation of Na(+),K(+)-ATPase. Signalling molecules and effectors can be integrated into a functional network by the scaffold organizer protein PATJ via its multiple PDZ domains.
    British Journal of Pharmacology 07/2009; 158(2):486-93. DOI:10.1111/j.1476-5381.2009.00299.x · 4.84 Impact Factor
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    Alejandro Mario Bertorello · Jian-Kang Zhu ·
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    ABSTRACT: Changes in cellular ion levels can modulate distinct signaling networks aimed at correcting major disruptions in ion balances that might otherwise threaten cell growth and development. Salt-inducible kinase 1 (SIK1) and salt overly sensitive 2 (SOS2) are key protein kinases within such networks in mammalian and plant cells, respectively. In animals, SIK1 expression and activity are regulated in response to the salt content of the diet, and in plants SOS2 activity is controlled by the salinity of the soil. The specific ionic stress (elevated intracellular sodium) is followed by changes in intracellular calcium; the calcium signals are sensed by calcium-binding proteins and lead to activation of SIK1 or SOS2. These kinases target major plasma membrane transporters such as the Na(+),K(+)-ATPase in mammalian cells, and Na(+)/H(+) exchangers in the plasma membrane and membranes of intracellular vacuoles of plant cells. Activation of these networks prevents abnormal increases in intracellular sodium concentration.
    Pflügers Archiv - European Journal of Physiology 03/2009; 458(3):613-9. DOI:10.1007/s00424-009-0646-2 · 4.10 Impact Factor
  • Pedro J. Chedrese · Alejandro M. Bertorello ·
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    ABSTRACT: Extracellular regulatory molecules convey information into the cell through a fast low energy complex of signals known as intracellular signaling pathways. The function of the pathways is to organize and amplify the signals in a way that a small number of ligands bound to receptors affect the activity of a large number of intracellular molecules. Signaling molecules can be divided into two main groups: the intracellular messengers and homology domain proteins.
    Reproductive Endocrinology, 12/2008: pages 23-39;

Publication Stats

4k Citations
586.40 Total Impact Points


  • 1989-2015
    • Karolinska Institutet
      • • Department of Biosciences and Nutrition
      • • Department of Neuroscience
      • • Department of Medical Biochemistry and Biophysics
      • • Pediatric Division
      Solna, Stockholm, Sweden
  • 1994-2014
    • Karolinska University Hospital
      • • Center for Molecular Medicine (CMM)
      • • Endocrinology Unit
      Tukholma, Stockholm, Sweden
  • 2000-2005
    • University of Chicago
      • Department of Medicine
      Chicago, Illinois, United States
  • 2003-2004
    • Northwestern University
      • Division of Pulmonary and Critical Care
      Evanston, Illinois, United States
    • University of Buenos Aires
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2002-2003
    • University of Houston
      • College of Pharmacy
      Houston, TX, United States
  • 1999
    • Saint Michael's Medical Center
      Newark, New Jersey, United States
  • 1987
    • Capio S:t Görans sjukhus
      Tukholma, Stockholm, Sweden