This review summarizes the data on the functional significance of ubiquitous(NKCC1)and renal-specific(NKCC2)isoforms of electroneutral sodium,potassium and chloride cotransporters.These carriers contribute to the path...This review summarizes the data on the functional significance of ubiquitous(NKCC1)and renal-specific(NKCC2)isoforms of electroneutral sodium,potassium and chloride cotransporters.These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid,respectively.Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume.However,the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.展开更多
During the last two decadesnumerous research teams demonstratedthat skeletalmuscles function as an exercise-dependent endocrine organ secreting dozens of myokines.Variety of physiological and pathophysiological implic...During the last two decadesnumerous research teams demonstratedthat skeletalmuscles function as an exercise-dependent endocrine organ secreting dozens of myokines.Variety of physiological and pathophysiological implications of skeletalmusclemyokines secretion has been described;however,upstream signals and sensing mechanisms underlying this phenomenon remain poorly understood.It is well documented that in skeletal muscles intensive exercise triggers dissipation of transmembrane gradient of monovalent cations caused by permanent activation of voltage-gated Nat and Kt channels.Recently,we demonstrated that sustained elevation of the[Nat]i/[Kt]i ratio triggers expression of dozens ubiquitous genes including several canonical myokines,such as interleukin-6 and cyclooxygenase 2,in the presence of intra-and extracellular Ca2t chelators.These data allowed us to suggest a novel[Nat]i/[Kt]i-sensitive,Ca2t i-independent mechanism of excitation-transcription coupling which triggers myokine production.This pathway exists in parallel with canonical signaling mediated by Ca2t i,AMP-activated protein kinase and hypoxia-inducible factor 1a(HIF-1a).In ourmini-reviewwe briefly summarize data supporting this hypothesis as well as unresolved issues aiming to forthcoming studies.展开更多
With an exception of few reports,the plasma concentration of ouabain and mari-nobufagenin,mostly studied cardiotonic steroids(CTS)assessed by immunoassay techniques,is less than 1 nM.During the last 3 decades,the impl...With an exception of few reports,the plasma concentration of ouabain and mari-nobufagenin,mostly studied cardiotonic steroids(CTS)assessed by immunoassay techniques,is less than 1 nM.During the last 3 decades,the implication of these endogenous CTS in the path-ogenesis of hypertension and other volume-expanded disorders is widely disputed.The threshold for inhibition by CTS of human and rodent a1-Na,K-ATPase is~1 and 1000 nM,respectively,that rules out the functioning of endogenous CTS(ECTS)as natriuretic hormones and regulators of cell adhesion,cell-to-cell communication,gene transcription and transla-tion,which are mediated by dissipation of the transmembrane gradients of monovalent cat-ions.In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase,decrease the[Na^(+)]i;/[K^(+)]i;-ratio and increase cell pro-liferation.Possible physiological significance and mechanism of non-canonical Na^(+)/K^(+)-depen-dent and Nai^(+)/Ki^(+)independent cell responses to CTS are discussed.展开更多
基金This work was supported by grants from the Canadian Institutes for Health Research(MOP-81392)(S.N.O.)Russian Foundation for Fundamental Research##14-04-31705(S.V.K.),15-04-00101(S.N.O.)+1 种基金the Russian Scientific Foundation#14-15-00006(S.N.O.)the USA National Institutes of Health Award R01-GM85058(N.O.D.).
文摘This review summarizes the data on the functional significance of ubiquitous(NKCC1)and renal-specific(NKCC2)isoforms of electroneutral sodium,potassium and chloride cotransporters.These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid,respectively.Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume.However,the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.
基金This work was supported by grants from the Canadian Institutes for Health Research(MOP-81392)the Kidney Foundation of Canada,the Heart and Stroke Foundation of Canada,Russian Foundation for Fundamental Research(15-04-00101)+1 种基金the Russian Scientific Foundation(14-15-00006)Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000430(N.O.D).
文摘During the last two decadesnumerous research teams demonstratedthat skeletalmuscles function as an exercise-dependent endocrine organ secreting dozens of myokines.Variety of physiological and pathophysiological implications of skeletalmusclemyokines secretion has been described;however,upstream signals and sensing mechanisms underlying this phenomenon remain poorly understood.It is well documented that in skeletal muscles intensive exercise triggers dissipation of transmembrane gradient of monovalent cations caused by permanent activation of voltage-gated Nat and Kt channels.Recently,we demonstrated that sustained elevation of the[Nat]i/[Kt]i ratio triggers expression of dozens ubiquitous genes including several canonical myokines,such as interleukin-6 and cyclooxygenase 2,in the presence of intra-and extracellular Ca2t chelators.These data allowed us to suggest a novel[Nat]i/[Kt]i-sensitive,Ca2t i-independent mechanism of excitation-transcription coupling which triggers myokine production.This pathway exists in parallel with canonical signaling mediated by Ca2t i,AMP-activated protein kinase and hypoxia-inducible factor 1a(HIF-1a).In ourmini-reviewwe briefly summarize data supporting this hypothesis as well as unresolved issues aiming to forthcoming studies.
基金supported by grants from the Russian Science Foundation#19-75-10009-E.A.K.the Russian Foundation for Basic Research(#18-04-00063-S.N.O.,#18-34-00308-A.M.T.)+1 种基金the National Institutes of Health Award 1R56HL127395(N.O.D.)National Center For Advancing Translational Sciences of the National Institutes of Health Award UL1TR000430(N.O.D.)。
文摘With an exception of few reports,the plasma concentration of ouabain and mari-nobufagenin,mostly studied cardiotonic steroids(CTS)assessed by immunoassay techniques,is less than 1 nM.During the last 3 decades,the implication of these endogenous CTS in the path-ogenesis of hypertension and other volume-expanded disorders is widely disputed.The threshold for inhibition by CTS of human and rodent a1-Na,K-ATPase is~1 and 1000 nM,respectively,that rules out the functioning of endogenous CTS(ECTS)as natriuretic hormones and regulators of cell adhesion,cell-to-cell communication,gene transcription and transla-tion,which are mediated by dissipation of the transmembrane gradients of monovalent cat-ions.In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase,decrease the[Na^(+)]i;/[K^(+)]i;-ratio and increase cell pro-liferation.Possible physiological significance and mechanism of non-canonical Na^(+)/K^(+)-depen-dent and Nai^(+)/Ki^(+)independent cell responses to CTS are discussed.