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B C Kone

Publications and source records attributed to B C Kone.

At least 19 recordsLinked to original sources
PubMed2005

Differential induction of PPAR-gamma by luminal glutamine and iNOS by luminal arginine in the rodent postischemic small bowel.

Using a rodent model of gut ischemia-reperfusion (I/R), we have previously shown that the induction of inducible nitric oxide synthase (iNOS) is harmful, whereas the induction of heme oxygenase 1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is protective. In the present study, we hypothesized that the luminal nutrients arginine and glutamine differentially modulate these molecular events in the postischemic gut. Jejunal sacs were created in rats at laparotomy, filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 min of superior mesenteric artery occlusion and 6 h of reperfusion, and compared with shams. The jejunum was harvested for histology or myeloperoxidase (MPO) activity (inflammation). Heat shock proteins and iNOS were quantitated by Western blot analysis and PPAR-gamma by DNA binding activity. In some experiments, rats were pretreated with the PPAR-gamma inhibitor G9662 or with the iNOS inhibitor N-[3(aminomethyl)benzyl]acetamidine (1400W). iNOS was significantly increased by arginine but not by glutamine following gut I/R and was associated with increased MPO activity and mucosal injury. On the other hand, PPAR-gamma was significantly increased by glutamine but decreased by arginine, whereas heat shock proteins were similarly increased in all experimental groups. The PPAR-gamma inhibitor G9662 abrogated the protective effects of glutamine, whereas the iNOS inhibitor 1400W attenuated the injurious effects of arginine. We concluded that luminal arginine and glutamine differentially modulate the molecular events that regulate injurious I/R-mediated gut inflammation and injury. The induction of PPAR-gamma by luminal glutamine is a novel protective mechanism, whereas luminal arginine appears harmful to the postischemic gut due to enhanced expression of iNOS.

Animals↗
PubMed2003

Protein-protein interactions involving inducible nitric oxide synthase.

AIM: Nitric oxide (NO) is a signaling and effector molecule that contributes to multiple physiological and pathophysiological processes in the kidney, vasculature, and other tissues. High output NO generation by inducible NO synthase (iNOS) participates in host defense against pathogens and contributes to tissue injury during inflammatory states. Because of its potent reactivity and diffusibility, NO generation by iNOS is subject to multiple levels of regulation, including transcriptional, translational, and post-translational controls, including protein-protein interactions. This review examines the experimental basis for these protein-protein interactions and their known and potential importance for kidney and vascular physiology. METHODS: Analysis of the biomedical literature in the area. RESULTS: iNOS interacts with the inhibitory molecules Kalirin and NOS-associated protein 1.10 kd (NAP110), which inhibit iNOS homodimerization, as well as activator proteins, the Rac-GTPases. Interactions with caveolin-1 control the intracellular locale and degradation of iNOS in tumor cells. In polarized epithelial cells, associations of iNOS with the scaffolding protein EBP50 position iNOS in the apical membrane near key ion transport proteins that also interact with EPB50. In addition, protein-protein interactions of proteins governing iNOS transcription function to specify activation or suppression of iNOS induction by cytokines. CONCLUSION: Interactions of iNOS with a diverse group of heterologous proteins provides a selective mechanism to control the activity, spatial distribution, and proximity of iNOS to intended targets, while potentially limiting autotoxicity to the iNOS-expressing cell.

Blood Proteins↗
PubMed2001

Molecular biology of natriuretic peptides and nitric oxide synthases.

Natriuretic peptides and nitric oxide play important roles in cardiovascular and renal physiology and disease. The natriuretic peptides - atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide - comprise a family of proteins that participate in the integrated control of intravascular volume and arterial blood pressure. The natriuretic peptides differentially bind distinct classes of receptors that signal through different mechanisms. Membrane-bound, guanylyl cyclase-coupled natriuretic peptide receptors (A- and B-types) mediate natriuretic peptide effects through the production of 3',5'-cyclic guanosine monophosphate (cGMP). C-Type natriuretic peptide receptors, which lack the guanylyl cyclase domain, alter target cell function through G(i) protein-coupled inhibition of membrane adenylyl cyclase activity, and also serve to clear circulating natriuretic peptides. The expression of the natriuretic peptides and their receptors are subject to complex controls. Similar structural and regulatory diversity exists for the nitric oxide synthases. The three nitric oxide synthase genes are regulated by a variety of mechanisms ranging from alternative splicing and alternative promoter usage to complex post-translational controls. This review highlights the molecular diversity of the natriuretic peptides and nitric oxide synthases and explores recent insights into their regulation.

Atrial Natriuretic Factor↗
PubMed2001

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Animals↗
PubMed2001

Specific association of nitric oxide synthase-2 with Rac isoforms in activated murine macrophages.

Nitric oxide synthase-2 (NOS2) is responsible for high-output nitric oxide production important in renal inflammation and injury. Using a yeast two-hybrid assay, we identified Rac2, a Rho GTPase member, as a NOS2-interacting protein. NOS2 and Rac2 proteins coimmunoprecipitated from activated RAW 264.7 macrophages. The two proteins colocalized in an intracellular compartment of these cells. Glutathione-S-transferase (GST) pull-down assays revealed that both Rac1 and Rac2 associated with GST-NOS2 and that the NOS2 oxygenase domain was necessary and sufficient for the interaction. [(35)S]methionine-labeled NOS2 interacted directly with GST-Rac2 in the absence of GTP, calmodulin, or NOS2 substrates or cofactors. Stable overexpression of Rac2 in RAW 264.7 cells augmented LPS-induced nitrite generation (~60%) and NOS2 activity (~45%) without measurably affecting NOS2 protein abundance and led to a redistribution of NOS2 to a high-speed Triton X-100-insoluble fraction. We conclude that Rac1 and Rac2 physically interact with NOS2 in activated macrophages and that the interaction with Rac2 correlates with a posttranslational stimulation of NOS2 activity and likely its spatial redistribution within the cell.

Animals↗
PubMed2000

Protein-protein interactions controlling nitric oxide synthases.

Nitric oxide (NO) biosynthesis is tightly regulated by a variety of mechanisms ranging from transcriptional to post-translational controls. Calmodulin has long been known to be an allosteric modulator of the three major NO synthases (NOS). Recent studies indicate that other proteins directly associate with NOS isoforms and regulate their activity or spatial distribution in the cell. Several proteins residing in or recruited to plasmalemmal caveolae of endothelial cells serve as allosteric regulators of endothelial NOS (eNOS). Caveolins, the resident scaffolding proteins of caveolae, and calmodulin undergo reciprocal Ca2+-dependent association and dissociation with eNOS in the caveolar membrane that inhibits (caveolins) and activates (calmodulin) eNOS activity. Other caveolar proteins appear to contribute to the eNOS-membrane complex, including the bradykinin B2 receptor, the angiotensin AT1 receptor, the CAT1 arginine transporter, and Hsp90. Direct interactions of a variety of proteins bearing PDZ domains with the PDZ domain of neuronal NOS (nNOS) have been shown to influence the subcellular distribution and/or activity of the enzyme in brain and muscle. One of these proteins, PSD-93, co-localizes with a subpopulation of nNOS in the macula densa. Although considerable emphasis has been placed on transcription as the principal step of regulation for inducible NOS (iNOS), our laboratory has recently defined a regulatory interaction of iNOS with Rho family GTPases. While the role of protein-eNOS interactions in the control of vascular tone has been increasingly clarified, the interactions and regulatory importance of protein association with nNOS and iNOS in the vasculature and kidney remains to be explored.

Animals↗
PubMed2000

alpha-MSH inhibits induction of C/EBPbeta-DNA binding activity and NOS2 gene transcription in macrophages.

BACKGROUND: alpha-Melanocyte-stimulating hormone (alpha-MSH) is an endogenous tridecapeptide that exerts anti-inflammatory actions and abrogates postischemic renal injury in rodents. alpha-MSH inhibits lipopolysaccharide (LPS)-induced gene expression of several cytokines, chemokines, and nitric oxide synthase-2 (NOS2), but the molecular mechanisms underlying these effects have not been clearly defined. To test the hypothesis that alpha-MSH inhibits the expression of inducible trans-activating factors involved in NOS2 regulation, we used RAW 264.7 macrophage cells to examine the effects of alpha-MSH on the activation of nuclear factor-kappaB (NF-kappaB) and CCAAT/enhancer binding protein-beta (C/EBPbeta), trans-acting factors known to be involved in LPS + interferon (IFN)-gamma induction of the NOS2 gene. METHODS: Gel shift assays were performed to identify NF-kappaB and C/EBP DNA binding activities in LPS + IFN-gamma-treated RAW 264.7 cells in the presence and absence of alpha-MSH. NOS2 promoter assays were conducted to identify the effects of alpha-MSH on LPS + IFN-gamma-mediated induction of NOS2 transcription. RESULTS: Gel shift assays demonstrated LPS + IFN-gamma induction of NF-kappaB and C/EBP family protein-DNA complexes in nuclei harvested from the cells. Supershift assays revealed that the C/EBP complexes were comprised of C/EBPbeta, but not C/EBPalpha, C/EBPdelta, or C/EBPepsilon. alpha-MSH (100 nmol/L) inhibited the LPS + IFN-gamma-mediated induction of nuclear DNA binding activity of C/EBPbeta, but not that of NF-kappaB (in contrast to reports in other cell types), as well as the activity of a murine NOS2 promoter-luciferase construct. In contrast, alpha-MSH (100 nmol/L) had no effect on the induction of NOS2 promoter-luciferase genes harboring deletion or mutation of the C/EBP box. CONCLUSIONS: These data indicate that alpha-MSH inhibits the induction of C/EBPbeta DNA binding activity and that this effect is a major mechanism by which alpha-MSH inhibits the transcription of the NOS2 gene. The inability of alpha-MSH to inhibit LPS + IFN-gamma induction of NF-kappaB in murine macrophage cells, which contrasts with inhibitory effects of the neuropeptide in other cell types, suggests that cell-type-specific mechanisms are involved.

Animals↗
PubMed2000

Sch-28080 depletes intracellular ATP selectively in mIMCD-3 cells.

Two H(+)-K(+)-ATPase isoforms are present in kidney: the gastric, highly sensitive to Sch-28080, and the colonic, partially sensitive to ouabain. Upregulation of Sch-28080-sensitive H(+)-K(+)-ATPase, or "gastric" H(+)-K(+)-ATPase, has been demonstrated in hypokalemic rat inner medullary collecting duct cells (IMCDs). Nevertheless, only colonic H(+)-K(+)-ATPase mRNA and protein abundance increase in this condition. This study was designed to determine whether Sch-28080 inhibits transporters other than the gastric H(+)-K(+)-ATPase. In the presence of bumetanide, Sch-28080 (200 microM) and ouabain (2 mM) inhibited (86)Rb(+) uptake (>90%). That (86)Rb(+) uptake was almost completely abolished by Sch-28080 indicates an effect of this agent on the Na(+)-K(+)-ATPase. ATPase assays in membranes, or lysed cells, demonstrated sensitivity to ouabain but not Sch-28080. Thus the inhibitory effect of Sch-28080 was dependent on cell integrity. (86)Rb(+)-uptake studies without bumetanide demonstrated that ouabain inhibited activity by only 50%. Addition of Sch-28080 (200 microM) blocked all residual activity. Intracellular ATP declined after Sch-28080 (200 microM) but recovered after removal of this agent. In conclusion, high concentrations of Sch-28080 inhibit K(+)-ATPase activity in mouse IMCD-3 (mIMCD-3) cells as a result of ATP depletion.

Adenosine Triphosphate↗
PubMed2000

How will gene therapy apply to the kidney in the 21st century?

Nephrology is entering the age of genomics-based drug discovery and development. Once only a theoretical objective, gene therapy is now being tested in various diseases. New and substantially improved vector systems and related technologies are undergoing development, many have shown promise in animal studies, and some are now being used in clinical trials. Recent advances in the molecular basis for renal diseases, organ transplant rejection, and hypertension have led to preclinical tests of gene therapeutic approaches. The most impressive of these strategies will likely soon be studied in the clinic. This review details recent advances in gene therapy technology and highlights potential novel applications of gene therapy in the treatment of renal diseases and hypertension. While the manufacture and widespread use of gene therapy products as conventional pharmaceuticals for renal diseases and hypertension may seem to be a goal for the remote future, much of the needed genetic information, technology, and intellectual resources are rapidly becoming available.

Animals↗
PubMed1999

CCAAT/enhancer binding protein-beta trans-activates murine nitric oxide synthase 2 gene in an MTAL cell line.

Nitric oxide production by nitric oxide synthase 2 (NOS2) has been implicated in epithelial cell injury from oxidative and immunologic stress. The NOS2 gene is transcriptionally activated by lipopolysaccharide (LPS) and cytokines in medullary thick ascending limb of Henle's loop (MTAL) cells and other cell types. The 5'-flanking region of the NOS2 gene contains a consensus element for CCAAT/enhancer binding proteins (C/EBP) at -150 to -142 that we hypothesized contributes to NOS2 trans-activation in the mouse MTAL cell line ST-1. Gel shift assays demonstrated LPS + interferon-gamma (IFN-gamma) induction of C/EBP family protein-DNA complexes in nuclei harvested from the cells. Supershift assays revealed that the complexes were comprised of C/EBPbeta, but not C/EBPalpha, C/EBPdelta, or C/EBPepsilon. NOS2 promoter-luciferase genes harboring deletion or mutation of the C/EBP box exhibited lower activities in response to LPS + IFN-gamma compared with wild-type NOS2 promoter constructs. Overexpression of a C/EBP-specific dominant-negative mutant limited LPS + IFN-gamma activation of the NOS2 promoter. In trans-activation assays, overexpression of C/EBPbeta stimulated basal NOS2 promoter activity. Thus C/EBPbeta appears to be an important trans-activator of the NOS2 gene in the MTAL.

Animals↗
PubMed1999

Nitric oxide inhibits transcription of the Na+-K+-ATPase alpha1-subunit gene in an MTAL cell line.

Nitric oxide (NO) has been implicated as an autocrine modulator of active sodium transport. To determine whether tonic exposure to NO influences active sodium transport in epithelial cells, we established transfected medullary thick ascending limb of Henle (MTAL) cell lines that overexpressed NO synthase-2 (NOS2) and analyzed the effects of deficient or continuous NO production [with or without NG-nitro-L-arginine methyl ester (L-NAME) in the culture medium, respectively] on Na+-K+-ATPase function and expression. The NOS2-transfected cells exhibited high-level NOS2 expression and NO generation, which did not affect cell viability or cloning efficiency. NOS2-transfected cells were grown in the presence of vehicle, NG-nitro-D-arginine methyl ester (D-NAME), or L-NAME for 16 h, after which 86Rb+ uptake assays, Northern analysis, or nuclear run-on transcription assays were performed. The NOS2-transfected cells allowed to produce NO continuously (vehicle or D-NAME) exhibited lower rates of ouabain-sensitive 86Rb+ uptake ( approximately 65%), lower levels of Na+-K+-ATPase alpha1-subunit mRNA ( approximately 60%), and reduced rates of de novo Na+-K+-ATPase alpha1-subunit transcription compared with L-NAME-treated cells. These results have uncovered a novel effect of NO to inhibit transcription of the Na+-K+-ATPase alpha1-subunit gene.

Animals↗
PubMed1999

Localization and regulation of nitric oxide synthase isoforms in the kidney.

Nitric oxide synthases (NOS), which comprise a multi-gene family, play important roles in a variety of physiological and pathophysiological processes in the kidney. The three major NOS isoforms are expressed in a cell type--specific manner and are subject to complex and distinct control mechanisms. Although knowledge about the intrarenal distribution and regulation of the major NOS isoforms has been expanding, recent advances in the molecular details of the structure, function, and regulation of the NOS genes and the enzymes they encode have added considerable complexity to the effort. Molecular biological studies have identified alternative splice variants of NOS1 and NOS2 that appear to be subject to unique regulation and may encode functionally distinct proteins. The renal distribution of these new variants has yet to be explored in detail. In addition, newly discovered transcriptional and posttranscriptional control mechanisms, including alternative promoter usage, protein-protein interactions, and phosphorylation events, for the three major NOS isoforms await characterization in renal cells. This review highlights the current state of knowledge about the distribution and regulation of the NOS isoforms in the kidney, and identifies new opportunities for further renal investigation.

Animals↗
PubMed1998

A novel N-terminal splice variant of the rat H+-K+-ATPase alpha2 subunit. Cloning, functional expression, and renal adaptive response to chronic hypokalemia.

The H+-K+-ATPase of renal collecting duct mediates K+ conservation during chronic hypokalemia. K+ deprivation promotes H+-K+-ATPase alpha2 (HKalpha2) gene expression in the medullary collecting duct, the principal site of active K+ reabsorption, suggesting that this isozyme contributes to renal K+ reclamation. We report here that alternative transcriptional initiation and mRNA splicing give rise to distinct N-terminal variants of the HKalpha2 subunit. Sequence analysis and in vitro translation revealed that HKalpha2a corresponds to the known HKalpha2 cDNA (Crowson, M. S., and Shull, G. E. (1992) J. Biol. Chem. 267, 13740-13748), whereas HKalpha2b represents a novel variant truncated by 108 amino acids at its N terminus. HKalpha2b mRNA contains a complex 5'-untranslated region with eight upstream open reading frames, features implicated in translational regulation of other genes. Heterologous expression of HKalpha2b with and without the gastric H+-K+-ATPase beta subunit in HEK 293 cells indicated that this variant encodes a K+ uptake mechanism that is relatively Sch 28080-resistant, partially sensitive to ouabain, and appears to require coexpression with the gastric H+-K+-ATPase beta subunit for optimal functional activity. Northern analysis demonstrated that both subtypes (HKalpha2b > HKalpha2a) are expressed abundantly in distal colon and modestly in proximal colon and kidney. Moreover, the abundance of the two mRNAs increases coordinately among the renal zones, but not in colon, with chronic K+ deprivation. These results demonstrate the potential for complex control of HKalpha2 gene expression by transcriptional and posttranscriptional mechanisms not recognized in other members of the Na+-K+-ATPase/H+-K+-ATPase family.

Alternative Splicing↗
PubMed1998

Molecular approaches to renal physiology and therapeutics.

The recent development of methods to transfer, mutate, or ablate genes in vivo has provided renal investigators and physicians with powerful tools to explore normal renal physiology, the pathophysiological basis of renal disease, and potential therapeutic interventions. The use of transgenic and knockout mice to produce gain-of-function and loss-of-function mutations, and to create animal models of human hereditary renal diseases, permits unprecedented versatility and power of experimental design. Conditional and inducible gene targeting methods to control the temporal and spatial expression of transgenes offer considerable promise in studying the impact of normal and disease genes in the kidney. In vivo gene transfer of encoding DNAs, antisense DNA and RNA, and cis-element decoys allows manipulation of specific genes in somatic cells. Liposome-mediated, virally mediated, and ex vivo transduced renal cells represent novel approaches to facilitate in vivo gene transfer to the kidney.

Animals↗
PubMed1997

Nitric oxide in renal health and disease.

Nitric oxide (NO) is a labile radical gas that is widely acclaimed as one of the most important molecules in biology. Through covalent modifications of target proteins and redox reactions with oxygen and superoxide radical and transition metal prosthetic groups, NO plays a critical role in many vital biological processes, including the control of vascular tone, neurotransmission, ventilation, hormone secretion, inflammation, and immunity. Moreover, NO has been shown to influence a host of fundamental cellular functions, such as RNA synthesis, mitochondrial respiration, glycolysis, and iron metabolism. NO is formed from L-arginine by NO synthases (NOSs), a family of related enzymes encoded by separate unlinked genes. The different NOS isozymes exhibit disparate tissue and intrarenal distributions and are governed by unique regulatory mechanisms. In the kidney, NO participates in several vital processes, including the regulation of glomerular and medullary hemodynamics, the tubuloglomerular feedback response, renin release, and the extracellular fluid volume. While NO serves beneficial roles as a messenger and host defense molecule, excessive NO production can be cytotoxic, the result of NO's reaction with reactive oxygen and nitrogen species, leading to peroxynitrite anion formation, protein tyrosine nitration, and hydroxyl radical production. Indeed, NO may contribute to the evolution of several commonly encountered renal diseases, including immune-mediated glomerulonephritis, postischemic renal failure, radiocontrast nephropathy, obstructive nephropathy, and acute and chronic renal allograft rejection. Moreover, impaired NO production has been implicated in the pathogenesis of volume-dependent hypertension. This duality of NO's beneficial and detrimental effects has created extraordinary interest in this molecule and the need for a detailed understanding of NO biosynthesis.

Acute Kidney Injury↗
PubMed1997

Biosynthesis and homeostatic roles of nitric oxide in the normal kidney.

Nitric oxide (NO) is an important molecular mediator of numerous physiological processes in virtually every organ. In the kidney, NO plays prominent roles in the homeostatic regulation of glomerular, vascular, and tubular function. Differential expression and regulation of the NO synthase (NOS) gene family contribute to this diversity of action. This review explores recent advances in the molecular and cell biology of the NOS isoforms and relates these findings to functions of NO in the control of normal renal hemodynamics, the glomerular microcirculation, and renal salt excretion. Newly recognized molecular diversity of the NOS gene products, factors governing NOS isozyme gene expression and catalytic activity, and the intrarenal distribution of the NOS isoforms are examined. Physiological data regarding the complex roles of NO in the control of renal hemodynamics and the glomerular microcirculation are analyzed, and the effects of chronic NOS inhibition on glomerular function and structure are presented. The contributions of NO to renal salt excretion as well as functional and molecular biological evidence for adaptive changes in NOS isoform expression during variations in dietary salt balance are discussed. Current investigative challenges and goals for future research of renal NO biology are presented.

Animals↗
PubMed1996

Functional expression of the colonic H+,K+-ATPase alpha-subunit. Pharmacologic properties and assembly with X+,K+-ATPase beta-subunits.

The functional and pharmacological properties of the alpha-subunit of the colonic H+,K+-ATPase (alphaC) were studied in Xenopus laevis oocytes. alphaC was injected with different rat beta-subunits, the beta-subunit of the gastric H+,K+-ATPase (betaG, the only H+, K+-ATPase beta-subunit identified in rat), or the beta1-subunit of the Na+,K+-ATPase (beta1) (associated with the basolateral Na+, K+-ATPase, but also expressed in the epithelial apical membranes of rat distal colon) (Marxer, A., Stieger, B., Quarini, A., Kashgarian, M., and Hauri, H. P. (1989) J. Cell Biol. 109, 1057-1069). The effect of the different beta-subunits was studied by measuring 86Rb+ uptake (a K+ congener) in the presence or absence of Sch-28080 and ouabain. Significant Na+-independent 86Rb+ uptake was observed only when alphaC was coexpressed with one of the beta-subunits. The expressed alphaCbeta1 and alphaCbetaG complexes were not inhibited by Sch-28080, were only partially sensitive to ouabain (IC50 = 400-600 microM, in the presence of external 1 mM KCl), and exhibited comparable K+ activation kinetics. Coexpression of alphaC with epitope-tagged betaG or beta1, followed by immunopurification of the alphabeta complexes, confirmed stable assembly of alphaCbetaG and alphaCbeta1 complexes. Since the beta1-subunit, but not the alpha1-subunit, of Na+,K+-ATPase is expressed in the apical membrane of rat colonocytes, our data support the view that, in rat distal colon, the beta1-subunit may play a surrogate role as the beta-subunit for the colonic H+,K+-ATPase.

Animals↗