COMT and MAO-A Polymorphisms and Obsessive-Compulsive Disorder: A Family-Based Association Study

ObjectiveObsessive-compulsive disorder (OCD) is a common and debilitating psychiatric illness. Although a genetic component contributes to its etiology, no single gene or mechanism has been identified to the OCD susceptibility. the catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) genes have been investigated in previous OCD studies, but the results are still unclear. More recently, Taylor (2013) in a comprehensive meta-analysis of genetic association studies has identified COMT and MAO-A polymorphisms involved with OCD. in an effort to clarify the role of these two genes in OCD vulnerability, a family-based association investigation was performed as an alternative strategy to the classical case-control design.MethodsTransmission disequilibrium analyses were performed after genotyping 13 single-nucleotide polymorphisms (eight in COMT and five in MAO-A) in 783 OCD trios (probands and their parents). Four different OCD phenotypes (from narrow to broad OCD definitions) and a SNP x SNP epistasis were also analyzed.ResultsOCD, broad and narrow phenotypes, were not associated with any of the investigated COMT and MAO-A polymorphisms. in addition, the analyses of gene-gene interaction did not show significant epistatic influences on phenotype between COMT and MAO-A.ConclusionsThe findings do not support an association between DSM-IV OCD and the variants of COMT or MAO-A. However, results from this study cannot exclude the contribution of these genes in the manifestation of OCD. the evaluation of broader spectrum phenotypes could help to understand the role of these and other genes in the pathophysiology of OCD and its spectrum disorders.Brazilian governmental agenciesConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundo de Aprimoramento Academico (FUAA-Grant for Academic Improvement)Department of Psychiatry University of São Paulo School of MedicineUniv São Paulo, Fac Med, Dept & Inst Psychiat, São Paulo, SP, BrazilUniv Fed Bahia, Serv Med Univ, Salvador, BA, BrazilUniv Pernambuco, Fac Ciencias Med, Recife, PE, BrazilUniversidade Federal de São Paulo, São Paulo, SP, BrazilBritish Columbia Mental Hlth & Addict Res Inst, Vancouver, BC, CanadaMassachusetts Gen Hosp, PNGU, Boston, MA 02114 USAMassachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USAUniv Calif San Francisco, Dept Psychiat, San Francisco, CA USAHosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, CanadaUniv Michigan, Dept Psychiat, Ann Arbor, MI 48109 USASunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, CanadaUniv Toronto, Ctr Addict & Mental Hlth, Toronto, ON, CanadaUniv Fed Rio de Janeiro, Inst Psiquiatria, IPUB, Programa Ansiedade & Depressao, Rio de Janeiro, BrazilUniv São Paulo, Inst Math & Stat, Dept Stat, São Paulo, SP, BrazilUniversidade Federal de São Paulo, São Paulo, SP, BrazilCNPq: 573974/2008-0FAPESP: 2005/55628-08FAPESP: 2008/57896-8Web of Scienc

Sildenafil reduces polyuria in rats with lithium-induced NDI

Sanches TR, Volpini RA, Massola Shimizu MH, de Bragan a AC, Oshiro-Monreal F, Seguro AC, Andrade L. Sildenafil reduces polyuria in rats with lithium-induced NDI. Am J Physiol Renal Physiol 302: F216-F225, 2012. First published October 12, 2011; doi:10.1152/ajprenal.00439.2010.-Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; alpha-, beta-, and gamma-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, gamma-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESPFoundation for the Support of Research in the State of Sao Paulo)Foundation for the Support of Research in the State of Sao Paulo)Laboratorios de Investigacao Medica (LIMsLaboratorios de Investigacao Medica (LIMsMedical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSPMedical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSPUniversity of Sao Paulo School of Medicine) Hospital das ClinicasUniversity of Sao Paulo School of Medicine) Hospital das ClinicasConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPqNational Council for Scientific and Technological DevelopmentNational Council for Scientific and Technological Development) [134318/2006-4, 309430/2006-7, 302835/2009-1

Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression

Alexandre CS, Braganca AC, Shimizu MH, Sanches TR, Fortes MA, Giorgi RR, Andrade L, Seguro AC. Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression. Am J Physiol Renal Physiol 297: F916-F922, 2009. First published August 5, 2009; doi:10.1152/ajprenal.90256.2008.-Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodiumand water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg(2+) channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications

N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation

Campos R, Shimizu MH, Volpini RA, de Bragan a AC, Andrade L, Lopes FD, Olivo C, Canale D, Seguro AC. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 302: L640-L650, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00097.2011.-Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the alpha-subunit of the epithelial sodium channel (alpha-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, alpha-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo Research Foundation) [2009/50263-2, 2008/57243-4]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo Research Foundation)Brazilian Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq, National Council for Scientific and Technological Development) [309947/2009-0]Brazilian Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq, National Council for Scientific and Technological Development